CN110191705A - The method for the treatment of cancer - Google Patents

The method for the treatment of cancer Download PDF

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CN110191705A
CN110191705A CN201780078431.1A CN201780078431A CN110191705A CN 110191705 A CN110191705 A CN 110191705A CN 201780078431 A CN201780078431 A CN 201780078431A CN 110191705 A CN110191705 A CN 110191705A
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ret
subject
fusion
cancer
ret fusion
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林毅仁
普拉蒂克·S·穆尔塔尼
理查德·兰丁
鲁巴尔·A·帕特尔
珍妮弗·赖特·奥利弗
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Ignyta Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

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Abstract

Disclosed herein is the methods of the cancer for the treatment of subject, wherein known subject has at least one be genetically changed in RET, N- [3- [(6 including applying from therapeutically effective amount to subject, 7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2, fluoro- 1, the 1- dimethyl ethyl of 2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt.

Description

The method for the treatment of cancer
Cross reference to related applications
This application claims the equity for the U.S. Provisional Patent Application No. 62/428947 submitted on December 1st, 2016 and preferentially Its content is integrally incorporated herein by reference by power herein.
Invention field
The present invention relates to the subjects that treatment has cancer, the N- [3- including applying therapeutically effective amount to the subject [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) different evil of -3- Oxazolyl]-urea or its pharmaceutically acceptable salt.
Background technique
The failure of protein kinase (PK) is the mark of many diseases.Participate in most of oncogene and the original cancer base of human cancer Because encoding PK.The enhancing activity of PK is also related to many nonmalignant diseases, such as benign prostatic hyperplasis, familial adenomatosis, polyp Disease, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation relevant to atherosclerosis, pulmonary fibrosis, arthritis Glomerulonephritis and postoperative stenosis and restenosis.
PK also assists in the breeding of inflammatory conditions and virus and helminth.PK may also be in the morbidity machine of neurodegenerative disease It plays a major role in system and development.
For PK failure or imbalance referring generally to see, e.g. Current Opinion in Chemical Biology 1999,3:459-465。
The glial cell line-derived nerve trophic factors of RET proto-oncogene Codocyte external signal transduction molecule (GDNF) receptor tyrosine kinase of the member of family.Loss or RET mutation are related with the development of Hirschsprung " s disease, and function The acquisition that can be mutated is related with the development of various types of human cancers (including medullary carcinoma of thyroid gland).It is arranged again during transfection The rearrangement of the proto-oncogene (RET) of column is the potential driving mutation in cancer (including adenocarcinoma of lung) by new discovery.Therefore, it needs Develop the new paragon of the subject with RET inhibitor for treating with cancer.
Summary of the invention
Disclosed herein is the methods of the treating cancer in subject, wherein the subject is known to be had in RET extremely A few genetic change, N- [3- [(6, the 7- dimethoxy-4 's-quinoline azoles including applying therapeutically effective amount to the oncological patients Quinoline base) oxygen] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt received.
Detailed description of the invention
Fig. 1 is the figure of three curves, it is shown that the curve graph of experiment described in embodiment 1, wherein having implanted tool There is the animal of the cell of specified RET fusion to use N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea, dosage is 30mg/kg BID (rectangular), with carrier (circle) comparison.Carrier is given in circle representative；It is rectangular to represent in the mouse for being implanted into the cell with specified RET fusion Give N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (fluoro- 1,1- dimethyl second of 2,2,2- tri- Base) -3- isoxazolyl]-urea, dosage is 30mg/kg BID.
Fig. 2 is to show the RET- inhibitor initial treatment for participating in that I phase described in embodiment 4 and Ib phase are studiedRET merges the Waterfall plot of the best tumor response in positive subjects.
The RET- fusion that Fig. 3 is shown in the RET- inhibitor initial treatment with non-small cell lung cancer (NSCLC) is positive N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl second of 2,2,2- tri- in patient Base) -3- isoxazolyl]-urea anti-tumor activity Waterfall plot.Each bar shaped represents single patient (22 patients in total).Generation There are table the bar-shaped marks of the patient of CCDC6-RET fusion, PARD3-RET fusion or EML4-RET fusion to have specific fusion.It is surplus Remaining unmarked bar shaped represents the patient with KIF5B-RET fusion.Y-axis indicates the maximum hundred in target lesion summation from baseline Divide than variation.
Specific embodiment
Term " N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (fluoro- 1,1- bis- of 2,2,2- tri- Methylethyl) -3- isoxazolyl]-urea " refer to the compound with following chemical structure
Alternatively, the Compound nomenclature be 1- [3- [(6,7- dimethoxyquinazoline -4- base) oxygroup] phenyl] -3- [5- (1, 1,1- tri- fluoro- 2- methylpropane -2- base) isoxazole -3- base] urea, and it has been designated as chemical abstracts registry no 1188910- 76-0.The compound is alternatively referred to as " RXDX-105 " herein.The preparation of the compound is disclosed in U.S. Patent number 8,618, In 289, the disclosure of which is incorporated herein by reference in their entirety.
Unless the context clearly determines otherwise, otherwise singular "one", "an", and " described " draw including plural number With.For example, term " cell " includes one or more cells, including its mixture." A and/or B " is herein for wrapping Include all following alternative forms: " A ", " B ", " A or B " and " A and B ".As it is used herein, term " about " means provided Value add deduct in 10%, or be rounded up to immediate effective digital, in all cases include provided value.It is mentioning In the case where range, they include boundary value.
As it is used herein, term administering " refer to bioactivity group by including but is not limited to administration method below Close the delivering of object or preparation: oral, intravenous, intra-arterial, intramuscular, intraperitoneal, subcutaneous, intramuscular and local use or A combination thereof.
As it is used herein, term " at least one gene alteration " means and corresponding wild type gene or protein phase Than any variation of gene or protein sequence in one or more cells of subject.One or more molecular changes packets Include but be not limited to genetic mutation, gene magnification, splice variant, missing, insertion/deletion, gene rearrangement, single nucleotide variations (SNV), insertion and aberrant RNAs/protein expression.
Caused by term " cancer " as used herein refers to any pernicious and/or invasive growth or abnormal cell growth Tumour.Term " cancer " as used herein refers to for the cell for forming entity tumor, blood, marrow or lymphatic system cancer The entity tumor of type name.The example of entity tumor includes but is not limited to sarcoma and carcinoma.The example of hematologic cancers include but It is not limited to leukaemia, lymthoma and myeloma.Term " cancer " include but is not limited to originating from body concrete position it is primary Property cancer, the position since it diffuse to original preinvasive cancer after the metastatic cancer in the other portions, area of body, alleviation Recurrence and second of preinvasive cancer, second of preinvasive cancer are that have and the different types of the past cancer of the latter The new preinvasive cancer of the personnel of history.
Term " joint " as used herein and " with ... combine " mean and at least one other drug or medicament (for example, anticancer agent) applies therapeutic agent described herein together, and either sequence application is still administered simultaneously.For example, the term Including simultaneously, or in mutual several minutes or a few hours, or on the same day, or administer every other day, or in terms of daily or more weekly It administers therapeutic agent described herein in terms of weekly, while in the time or at least part time simultaneously or parallel It is applied separately during (administering therapeutic agent described herein during the time) on the same day or every other day or every other week or in terms of periodically A kind of compound, such as chemotherapeutant.
As it is used herein, the term " contact " used when referring to specificity or specific binding means two molecules It is close enough, so that short distance non-covalent chemical interacts, such as the bonding of Van der Waals force, hydrogen, the leading molecule of hydrophobic interaction Interaction.
As it is used herein, term " pharmaceutically acceptable salt " means to retain biological effectiveness and parent compound Those of characteristic salt.These salt include adding with the acid of inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid etc. At salt, or with organic acid such as acetic acid, trifluoroacetic acid, propionic acid, glycolic, (D) or (L) lactic acid, malic acid, maleic acid, methanesulfonic acid, Ethanesulfonic acid, benzoic acid, p-methyl benzenesulfonic acid, salicylic acid, cinnamic acid, mandelic acid, tartaric acid, citric acid, succinic acid, malonic acid etc. Acid-addition salts；The acid proton present in the compound is by metal ion (such as the alkali metal ions such as sodium or potassium or calcium or magnesium etc. Alkaline-earth metal ions) replace when or it is organic with ethanol amine, diethanol amine, triethanolamine, tromethamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc. The salt that alkali is formed when being coordinated.
The term " RET " used herein with gene-correlation refers to that those of ordinary skill in the art are known as Ret original cancer The gene of gene.The substitution title of RET gene known to persons of ordinary skill in the art include CDHF12, CDHR16, PTC and RET51.When used in connection with protein herein, term " RET " refers to that those of ordinary skill in the art are known as RET simultaneously And the wild-type protein with UniProt identifier RET_HUMAN (P07949).
Disclosed herein is the methods of the treating cancer in subject, wherein the subject is known to be had in RET extremely A few genetic change, N- [3- [(6, the 7- dimethoxy-4 's-quinazoline including giving oncological patients' therapeutically effective amount Base) oxygen] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its is pharmaceutically acceptable Salt.
In one embodiment, at least one of described RET genetic change is Gene Fusion or activation point mutation.
In one embodiment, at least one of described RET is genetically changed as activation point mutation.In an embodiment party In case, the activation point mutation is M918T point mutation.
In one embodiment, at least one of described RET genetic change is Gene Fusion.In an embodiment In, the Gene Fusion is selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion and PARD3- RET fusion.In one embodiment, Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In one embodiment, The Gene Fusion is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET fusion.
In one embodiment, at least one of described RET genetic change is Gene Fusion.In an embodiment In, the Gene Fusion is selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3- RET fusion and CLIP1-RET fusion.In one embodiment, Gene Fusion is NCOA4-RET fusion.In an embodiment party In case, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.? In one embodiment, the Gene Fusion is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET fusion.In one embodiment, the Gene Fusion is CLIP1-RET fusion.
In one embodiment, providing treatment has the method for subject of cancer, wherein the known tool of the cancer Have and is genetically changed at least one of RET, N- [3- [(6, the 7- diformazans including giving oncological patients' therapeutically effective amount Oxygroup -4- quinazolyl) oxygen] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its Pharmaceutically acceptable salt.In some embodiments, at least one of RET genetic change is Gene Fusion.In a reality It applies in scheme, the Gene Fusion is selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET is merged, EML4-RET is merged, PARD3-RET fusion and CLIP1-RET fusion.In one embodiment, Gene Fusion is NCOA4-RET fusion.At one In embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is that CCDC6-RET melts It closes.In one embodiment, the Gene Fusion is EML4-RET fusion.In one embodiment, the Gene Fusion It is PARD3-RET fusion.In one embodiment, the Gene Fusion is CLIP1-RET fusion.In an embodiment In, any method as described herein is provided, wherein the cancer in the subject is selected from colorectal cancer, lung cancer, non- Small Cell Lung Cancer, thyroid cancer and medullary carcinoma of thyroid gland.In one embodiment, the cancer in the subject is knot The intestines carcinoma of the rectum.In one embodiment, the colorectal cancer is metastatic colorectal cancer.In one embodiment, The cancer in the subject is lung cancer.In one embodiment, the cancer in the subject is non-small thin Born of the same parents' lung cancer.In one embodiment, the cancer in the subject is thyroid cancer.In one embodiment, institute The cancer stated in subject is medullary carcinoma of thyroid gland.In one embodiment, the cancer in the subject is Solid tumor or liquid tumors.In one embodiment, the cancer in the subject is solid tumor.In an embodiment party In case, the cancer in the subject is liquid tumors.In some embodiments, the subject suffers from RET Lung cancer at least one genetic change, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET The Gene Fusion of fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.Some In embodiment, the subject is with the lung cancer in RET at least one genetic change, wherein at least one something lost Passing change is CCDC6-RET fusion.In some embodiments, the subject suffers from has at least one heredity in RET The lung cancer of change, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, the subject With the lung cancer in RET at least one genetic change, wherein at least one be genetically changed is that PARD3-RET melts It closes.In some embodiments, the subject is with the lung cancer in RET at least one genetic change, wherein described It is CLIP1-RET fusion that at least one, which is genetically changed,.
In some embodiments, the subject is with the colorectum in RET at least one genetic change Cancer, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4- The Gene Fusion of RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, the subject suffers from There is the colorectal cancer being genetically changed in RET at least one, wherein at least one be genetically changed is CCDC6-RET Fusion.In some embodiments, the subject suffers from the colorectal cancer in RET at least one genetic change, Wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, the subject suffers from RET Colorectal cancer at least one genetic change, wherein at least one be genetically changed is PARD3-RET fusion.One In a little embodiments, the subject in RET with the colorectal cancer of at least one genetic change, wherein it is described extremely A kind of few genetic change is CLIP1-RET fusion.
In some embodiments, the subject is with the medullary thyroid in RET at least one genetic change Sample cancer, wherein it is described it is at least one be genetically changed be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, The Gene Fusion of EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, described tested Person is with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments, the subject is with the first in RET at least one genetic change Shape gland cephaloma, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, the subject With the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, the subject is with the first in RET at least one genetic change Shape gland cephaloma, wherein at least one be genetically changed is CLIP1-RET fusion.
In some embodiments, the subject suffers from the sarcoma in RET at least one genetic change, wherein It is described it is at least one be genetically changed be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, The Gene Fusion of PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, the subject suffers from RET Sarcoma at least one genetic change, wherein at least one be genetically changed is CCDC6-RET fusion.In some implementations In scheme, the subject is with the sarcoma in RET at least one genetic change, wherein at least one heredity changes Change is EML4-RET fusion.In some embodiments, the subject suffers from has at least one genetic change in RET Sarcoma, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, the subject suffers from With the sarcoma of at least one genetic change in RET, wherein at least one be genetically changed is CLIP1-RET fusion.
Any method as described herein is also provided herein, wherein the N- [3- [(6,7- dimethoxy-4 's-quinazoline Base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt received is applied to the subject with the amount of about 100mg to about 1000mg daily.In one embodiment, the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) different evil of -3- Oxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 100mg to about 900mg be daily applied to the subject.At one In embodiment, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] the phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, 1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt applied with the amount of about 100mg to about 800mg daily For the subject.In one embodiment, described N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] benzene Base]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be with every The amount of its about 100mg to about 700mg are applied to the subject.In one embodiment, N- [3- [(6, the 7- dimethoxies Base -4- quinazolyl) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its Pharmaceutically acceptable salt is applied to the subject with the amount of about 100mg to about 600mg daily.In one embodiment, N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl second of 2,2,2- tri- Base) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 100mg to about 500mg daily be applied to it is described by Examination person.In one embodiment, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] the phenyl]-N'- [5- (2, The fluoro- 1,1- dimethyl ethyl of 2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt with about 100mg daily to about The amount of 400mg is applied to the subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazoline Base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt received is applied to the subject with the amount of about 100mg to about 375mg daily.In one embodiment, the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) different evil of -3- Oxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 100mg to about 350mg be daily applied to the subject.At one In embodiment, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] the phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, 1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt applied with the amount of about 150mg to about 1000mg daily For the subject.In one embodiment, described N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] benzene Base]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be with every The amount of its about 175mg to about 1000mg are applied to the subject.In one embodiment, N- [3- [(6, the 7- diformazans Oxygroup -4- quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or Its pharmaceutically acceptable salt is applied to the subject with the amount of about 200mg to about 1000mg daily.In an embodiment In, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, the 1- dimethyl Ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be applied to the amount of about 225mg to about 1000mg daily it is described Subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt with about 175mg daily extremely The amount of about 800mg is applied to the subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazoline Base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt received is applied to the subject with the amount of about 275mg to about 350mg daily.In one embodiment, the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) different evil of -3- Oxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 200mg be daily applied to the subject.In an embodiment In, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, the 1- dimethyl Ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 225mg be daily applied to the subject.? In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be applied to the amount of about 250mg daily The subject.In one embodiment, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] the phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt are with daily about The amount of 275mg is applied to the subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazoline Base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt received is applied to the subject with the amount of about 300mg daily.In one embodiment, N- [3- [(6, the 7- diformazans Oxygroup -4- quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or Its pharmaceutically acceptable salt is applied to the subject with the amount of about 325mg daily.In one embodiment, the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 350mg be daily applied to the subject.Implement at one In scheme, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, the 1- bis- Methylethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be applied to the amount of about 375mg daily it is described tested Person.In one embodiment, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] the phenyl]-N'- [5- (2,2, The fluoro- 1,1- dimethyl ethyl of 2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt applied with the amount of about 400mg daily For the subject.In one embodiment, described N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] benzene Base]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be with every The amount of its about 425mg is applied to the subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinoline azoles Quinoline base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically may be used The salt of receiving is applied to the subject with the amount of about 450mg daily.In one embodiment, the N- [3- [(6,7- bis- Methoxyl group -4- quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea Or its pharmaceutically acceptable salt is applied to the subject with the amount of about 475mg daily.In one embodiment, the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 500mg be daily applied to the subject.
Any method as described herein is also provided herein, wherein the subject is in the eating state administered the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt.
Any method as described herein is also provided herein, wherein the subject is RET- inhibitor initial treatment. Any method as described herein is also provided herein, wherein the subject is not RET inhibitor initial treatment.
Any method as described herein is also provided herein, wherein the cancer in the subject is selected from colorectum Cancer, lung cancer, non-small cell lung cancer, thyroid cancer and medullary carcinoma of thyroid gland.In one embodiment, the institute in the subject Stating cancer is colorectal cancer.In one embodiment, the colorectal cancer is metastatic colorectal cancer.In a reality It applies in scheme, the cancer in the subject is lung cancer.In one embodiment, the cancer in the subject It is non-small cell lung cancer.In one embodiment, the cancer in the subject is thyroid cancer.In an embodiment party In case, the cancer in the subject is medullary carcinoma of thyroid gland.In one embodiment, described in the subject Cancer is solid tumor or liquid tumors.In one embodiment, the cancer in the subject is solid tumor.At one In embodiment, the cancer in the subject is liquid tumors.
Some embodiments of the invention are for treating the cancer including concrete type below: carcinoma, squamous cell carcinoma, Medullary system or lymphatic cells tumour, the tumour in mesenchyma source, tumour, melanoma, the essence original of maincenter and peripheral neverous system Cytoma, teratocarcinoma, osteosarcoma, angioderma pigmentosum, angiosarcoma, glioblastoma, cholangiocarcinoma, inflammatory muscle fibre Blastoma, epithelioid hemangioendothelioma, astrocytoma, meningioma, angiosarcoma, epithelioid pericytoma (epitheloidhemangiothelioma), keratoacanthoma, thyroid follcular carcinoma, Kaposi's sarcoma and cancer of pancreas.
Some embodiments of the invention are used to treat the cancer of concrete type such as, but not limited to, below: breast cancer, lung Cancer, colorectal cancer, prostate cancer, oophoroma, carcinoma of endometrium, gastric cancer, clear cell renal cell carcinoma, invasive ductal carcinoma (breast), uveal, Huppert's disease, rhabdomyosarcoma, ewing's sarcoma, Kaposi's sarcoma, cancer of pancreas And medulloblastoma.
Some embodiments of the invention are used to treat the cancer of concrete type such as, but not limited to, below: breast cancer, lung Cancer, colorectal cancer, prostate cancer, oophoroma, carcinoma of endometrium, gastric cancer, clear cell renal cell carcinoma, invasive ductal carcinoma (breast), uveal, Huppert's disease, rhabdomyosarcoma, ewing's sarcoma, Kaposi's sarcoma, cancer of pancreas And medulloblastoma.In some embodiments, lung cancer is Small Cell Lung Cancer or non-small cell lung cancer.In some embodiment party In case, cancer is Small Cell Lung Cancer.In some embodiments, cancer is non-small cell lung cancer.
Some embodiments of the invention are used for N- [3- [(the 6,7- dimethoxy-4 '-quinoline by application therapeutically effective amount Oxazoline base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically The acceptable salts for treating cancer that wherein the defects of active adjusting of RET or its up-regulation, misadjustment or missing may play a role Disease, mitigate its symptom, improve its symptom, postpone its breaking-out or otherwise pharmacy solve cancer.
Disclosed herein is by being administered to a effective amount of N- of subject [3- [(6,7- dimethoxy-4 '-quinazolyl) Oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its is pharmaceutically acceptable The salts for treating subject's that wherein the defects of active adjusting of RET or its up-regulation, misadjustment or missing may play a role Cancer and other possible signs mitigate its symptom, improve its symptom, postponing its breaking-out or otherwise pharmacy solution Its method.
In some embodiments, method of the invention is used in cancer or precancerous cell by identification subject RET lowers defect, such as null mutation such as RET missing, and is administered to a effective amount of N- of the subject [3- [(6,7- Dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl] - Urea or its pharmaceutically acceptable salt, treat the cancer of subject, mitigate its symptom, improve its symptom, postpone its breaking-out or Otherwise pharmacy solves cancer, and the cancer is related with RET downward defect, such as null mutation such as RET missing.
In some embodiments, it identifies that the RET before the cancer or cancer of subject in pancreatic cell adjusts defect, such as raises Defect lowers defect, such as null mutation, the RET mosaic gene of such as RET missing or the active RET kinases of encoding constitutive Seat, including the RET activity in cell extract of the measurement from cancer of pancreas or precancerous cell group.In some embodiments, it reflects Determine the RET before the cancer or cancer of subject in pancreatic cell and adjust defect, such as raise defect or lower defect, such as is invalid prominent Become, the RET mosaic gene seat of such as RET missing or the active RET kinases of encoding constitutive, including measurement come from cancer of pancreas or cancer RET transcript accumulation in the RNA group of preceding cell mass.In some embodiments, pancreas before the cancer or cancer of subject is identified RET in cell adjusts defect, such as raises defect or lowers defect, such as null mutation, such as RET missing or encoding constitutive The RET mosaic gene seat of active RET kinases, including measure one or more cells or comprising thin before cancer of pancreas or cancer Nucleic acid sequence in the cell mass of one or more cells of born of the same parents group, such as genomic dna sequence.
In some embodiments, method of the invention further comprises that the subject with cancer is made to be subjected to combining at least Radiotherapy or the chemotherapy regimen of a kind of cytostatic agent or cytotoxic agent.Inhibit RET protein living in addition, the present invention provides Property method, this method include make the protein and a effective amount of N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] Phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt connect Touching.
The method for inhibiting RET kinase activity in cell is also provided herein, including makes the cell and a effective amount of N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt contact.
The present invention also provides pharmaceutical compositions, and it includes the N- of therapeutically effective amount [3- [(6,7- dimethoxy-4 's-quinoline azoles Quinoline base) oxygen] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt and pharmaceutically acceptable excipient, carrier or diluent received.
There is disclosed herein inhibiting the active method of RET in subject, including to be administered to the subject a effective amount of N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt.
There is disclosed herein the methods of the treating cancer in the subject of needs, including by having to subject application N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (fluoro- 1,1- dimethyl second of 2,2,2- tri- of effect amount Base) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, inhibit the RET activity in the subject.
There is disclosed herein the method for the treating cancer in the subject of needs, the method includes by described tested Person applies a effective amount of N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (fluoro- 1,1- of 2,2,2- tri- Dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, inhibit the RET activity in the subject.
Some embodiments provide the lung cancer for the treatment of subjects, non-small cell lung cancer, thyroid cancer, medullary carcinoma of thyroid gland, Papillary thyroid carcinoma, neuroblastoma, the method for cancer of pancreas or colorectal cancer, wherein the known subject is in RET In have it is at least one be genetically changed, including apply a effective amount of N- [3- [(6,7- dimethoxy-4 's-quinoline azoles to the subject Quinoline base) oxygen] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt received.In one embodiment, at least one be genetically changed in RET is Gene Fusion or activation point mutation.? In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B-RET, CCDC6-RET fusion, EML4-RET fusion It is merged with PARD3-RET.In one embodiment, the activation point mutation is M918T point mutation.In an embodiment In, the Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET fusion.One In a embodiment, the Gene Fusion is CCDC6-RET fusion.In one embodiment, the Gene Fusion is EML4- RET fusion.In one embodiment, the Gene Fusion is PARD3-RET fusion.
Some embodiments provide the lung cancer for the treatment of subjects, non-small cell lung cancer, thyroid cancer, medullary carcinoma of thyroid gland, Papillary thyroid carcinoma, neuroblastoma, the method for cancer of pancreas or colorectal cancer, wherein the known subject is in RET In have it is at least one be genetically changed, including apply a effective amount of N- [3- [(6,7- dimethoxy-4 's-quinoline azoles to the subject Quinoline base) oxygen] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt received.In one embodiment, at least one be genetically changed in RET is Gene Fusion or activation point mutation.? In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B-RET, CCDC6-RET fusion, EML4-RET melts It closes, PARD3-RET fusion and CLIP1 are merged.In one embodiment, the activation point mutation is M918T point mutation.One In a embodiment, the Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET Fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In one embodiment, the gene melts Conjunction is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET fusion.In an embodiment In, the Gene Fusion is CLIP1-RET fusion.
It is effective the method includes being administered to the subject there is disclosed herein the method for treating tumour in subject N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (fluoro- 1,1- dimethyl second of 2,2,2- tri- of amount Base) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt.In one embodiment, it is known that the subject is in RET It is genetically changed at least one.In one embodiment, in RET it is described it is at least one be genetically changed be Gene Fusion or Activate point mutation.In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B-RET, CCDC6-RET and melts It closes, EML4-RET fusion and PARD3-RET are merged.In one embodiment, the activation point mutation is M918T point mutation. In one embodiment, the Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In one embodiment, The Gene Fusion is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET fusion.
It is effective the method includes being administered to the subject there is disclosed herein the method for treating tumour in subject N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (fluoro- 1,1- dimethyl second of 2,2,2- tri- of amount Base) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt.In one embodiment, it is known that the subject is in RET It is genetically changed at least one.In one embodiment, in RET it is described it is at least one be genetically changed be Gene Fusion or Activate point mutation.In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B-RET, CCDC6-RET and melts It closes, EML4-RET fusion, PARD3-RET is merged and CLIP1-RET fusion.In one embodiment, the activation point mutation It is M918T point mutation.In one embodiment, the Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In a reality It applies in scheme, the Gene Fusion is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET Fusion.In one embodiment, the Gene Fusion is CLIP1-RET fusion.
Some embodiments provide method, wherein the tumour is by lung cancer, non-small cell lung cancer, thyroid cancer, first Shape gland cephaloma, the presence of papillary thyroid carcinoma, neuroblastoma, cancer of pancreas or colorectal cancer in subject are drawn It rises.Some embodiments provide method, wherein gene of the one or more cells in subject comprising tumour to expression RET Presence test go out RET activity for one or more cells shows comprising tumour in the positive or described subject.
Some embodiments provide method, and wherein one or more cells in subject comprising tumour are for including At least one gene rearrangement test of RET or its segment, expression RET is the positive.
There is disclosed herein the methods of cancer in treatment subject, which comprises (1) includes swollen in test subject The presence of the RET of one or more cells of tumor；(2) it if one or more cell detections are RET positive, is administered to [(2,2,2- tri- is fluoro- by 5- by-N'- for a effective amount of N- of subject [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl] 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt.In one embodiment, it is known that described Subject has at least one be genetically changed in RET.In one embodiment, at least one heredity in RET changes Change is Gene Fusion or activation point mutation.In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B- RET, CCDC6-RET fusion, EML4-RET fusion and PARD3-RET fusion.In one embodiment, the activation point mutation It is M918T point mutation.In one embodiment, the Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In a reality It applies in scheme, the Gene Fusion is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET Fusion.
There is disclosed herein the methods of cancer in treatment subject, which comprises (1) includes swollen in test subject The presence of the RET of one or more cells of tumor；(2) it if one or more cell detections are RET positive, is administered to [(2,2,2- tri- is fluoro- by 5- by-N'- for a effective amount of N- of subject [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl] 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt.In one embodiment, it is known that described Subject has at least one be genetically changed in RET.In one embodiment, at least one heredity in RET changes Change is Gene Fusion or activation point mutation.In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B- RET, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In one embodiment, The activation point mutation is M918T point mutation.In one embodiment, the Gene Fusion is NCOA4-RET fusion.One In a embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET Fusion.In one embodiment, the Gene Fusion is EML4-RET fusion.In one embodiment, the gene melts Conjunction is PARD3-RET fusion.In one embodiment, the Gene Fusion is CLIP1-RET fusion.In an embodiment In, the Gene Fusion is CLIP1-RET fusion.In one embodiment, any method as described herein is provided, wherein The cancer in the subject is selected from colorectal cancer, lung cancer, non-small cell lung cancer, thyroid cancer and medullary thyroid sample Cancer.In one embodiment, the cancer in the subject is colorectal cancer.In one embodiment, described Colorectal cancer is metastatic colorectal cancer.In one embodiment, the cancer in the subject is lung cancer.? In one embodiment, the cancer in the subject is non-small cell lung cancer.In one embodiment, described tested The cancer in person is thyroid cancer.In one embodiment, the cancer in the subject is medullary thyroid sample Cancer.In one embodiment, the cancer in the subject is solid tumor or liquid tumors.In an embodiment In, the cancer in the subject is solid tumor.In one embodiment, the cancer in the subject is liquid Body tumour.In some embodiments, the subject suffers from the lung cancer in RET at least one genetic change, wherein It is described it is at least one be genetically changed be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, The Gene Fusion of PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, the subject suffers from RET Lung cancer at least one genetic change, wherein at least one be genetically changed is CCDC6-RET fusion.In some implementations In scheme, the subject is with the lung cancer in RET at least one genetic change, wherein at least one heredity changes Change is EML4-RET fusion.In some embodiments, the subject suffers from has at least one genetic change in RET Lung cancer, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, the subject suffers from With the lung cancer of at least one genetic change in RET, wherein at least one be genetically changed is CLIP1-RET fusion.? In some embodiments, the subject is with the colorectal cancer in RET at least one genetic change, wherein described At least one be genetically changed be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, The Gene Fusion of PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, the subject suffers from RET With the colorectal cancer that at least one is genetically changed, wherein at least one be genetically changed is CCDC6-RET fusion.One In a little embodiments, the subject in RET with the colorectal cancer of at least one genetic change, wherein it is described extremely A kind of few genetic change is EML4-RET fusion.In some embodiments, the subject suffers from has at least one in RET The colorectal cancer that kind is genetically changed, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments In, the subject is with the colorectal cancer in RET at least one genetic change, wherein at least one heredity Change is CLIP1-RET fusion.In some embodiments, the subject suffers from, and there is at least one heredity to change in RET The medullary carcinoma of thyroid gland of change, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET fusion, CCDC6- The Gene Fusion of RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, The subject is with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one heredity Change is CCDC6-RET fusion.In some embodiments, the subject suffers from, and there is at least one heredity to change in RET The medullary carcinoma of thyroid gland of change, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, described Subject is with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one genetic change It is PARD3-RET fusion.In some embodiments, the subject suffers from has at least one genetic change in RET Medullary carcinoma of thyroid gland, wherein at least one be genetically changed is CLIP1-RET fusion.In some embodiments, it is described by Examination person is with the sarcoma in RET at least one genetic change, wherein at least one be genetically changed is to be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET melt The Gene Fusion of conjunction.In some embodiments, the subject is with the meat in RET at least one genetic change Tumor, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments, the subject suffers from With the sarcoma of at least one genetic change in RET, wherein at least one be genetically changed is EML4-RET fusion.Some In embodiment, the subject is with the sarcoma in RET at least one genetic change, wherein at least one something lost Passing change is PARD3-RET fusion.In some embodiments, the subject suffers from has at least one heredity in RET The sarcoma of change, wherein at least one be genetically changed is CLIP1-RET fusion.
Some embodiments provide the method for subject of the treatment with cancer, including have to subject application treatment N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (fluoro- 1,1- dimethyl second of 2,2,2- tri- of effect amount Base) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, wherein before the application compound, it is known that described Subject has to be genetically changed at least one of RET.In one embodiment, at least one heredity in RET Change is Gene Fusion or activation point mutation.In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B- RET, CCDC6-RET fusion, EML4-RET fusion and PARD3-RET fusion.In one embodiment, the activation point mutation It is M918T point mutation.In one embodiment, the Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In a reality It applies in scheme, the Gene Fusion is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET Fusion.In one embodiment, any method as described herein is provided, wherein the cancer in the subject is selected from Colorectal cancer, lung cancer, non-small cell lung cancer, thyroid cancer and medullary carcinoma of thyroid gland.In one embodiment, described tested The cancer in person is colorectal cancer.In one embodiment, the colorectal cancer is metastatic colorectal cancer. In one embodiment, the cancer in the subject is lung cancer.In one embodiment, in the subject The cancer is non-small cell lung cancer.In one embodiment, the cancer in the subject is thyroid cancer.One In a embodiment, the cancer in the subject is medullary carcinoma of thyroid gland.In one embodiment, the subject In the cancer be solid tumor or liquid tumors.In one embodiment, the cancer in the subject is entity Tumor.In one embodiment, the cancer in the subject is liquid tumors.In some embodiments, it is described by Examination person is with the lung cancer in RET at least one genetic change, wherein at least one be genetically changed is to be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET melt The Gene Fusion of conjunction.In some embodiments, the subject is with the lung in RET at least one genetic change Cancer, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments, the subject suffers from With the lung cancer of at least one genetic change in RET, wherein at least one be genetically changed is EML4-RET fusion.Some In embodiment, the subject is with the lung cancer in RET at least one genetic change, wherein at least one something lost Passing change is PARD3-RET fusion.In some embodiments, the subject suffers from has at least one heredity in RET The lung cancer of change, wherein at least one be genetically changed is CLIP1-RET fusion.In some embodiments, described tested Person is with the colorectal cancer in RET at least one genetic change, wherein at least one be genetically changed is to be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET melt The Gene Fusion of conjunction.In some embodiments, the subject is with the colon at least one genetic change in RET The carcinoma of the rectum, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments, the subject suffers from There is the colorectal cancer in RET at least one genetic change, wherein at least one be genetically changed is EML4-RET Fusion.In some embodiments, the subject suffers from the colorectal cancer in RET at least one genetic change, Wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, the subject suffers from RET In the colorectal cancer at least one genetic change, wherein at least one be genetically changed is CLIP1-RET fusion.? In some embodiments, the subject suffers from the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein institute State it is at least one be genetically changed be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, The Gene Fusion of PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, the subject suffers from RET Medullary carcinoma of thyroid gland at least one genetic change, wherein at least one be genetically changed is CCDC6-RET fusion.? In some embodiments, the subject suffers from the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein institute Stating at least one be genetically changed is EML4-RET fusion.In some embodiments, the subject suffers from has extremely in RET The medullary carcinoma of thyroid gland of few a kind of genetic change, wherein at least one be genetically changed is PARD3-RET fusion.In some realities Apply in scheme, the subject in RET with the medullary carcinoma of thyroid gland of at least one genetic change, wherein it is described at least A kind of be genetically changed is CLIP1-RET fusion.In some embodiments, the subject suffers from has at least one in RET Kind of the sarcoma being genetically changed, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET fusion, CCDC6- The Gene Fusion of RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, The subject is with the sarcoma in RET at least one genetic change, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments, the subject is with the meat in RET at least one genetic change Tumor, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, the subject suffers from With the sarcoma of at least one genetic change in RET, wherein at least one be genetically changed is PARD3-RET fusion.One In a little embodiments, the subject is with the sarcoma in RET at least one genetic change, wherein at least one Genetic change is CLIP1-RET fusion.
Some embodiments provide the method for subject of the treatment with cancer, including have to subject application treatment N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (fluoro- 1,1- dimethyl second of 2,2,2- tri- of effect amount Base) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, wherein before the application compound, it is known that described Subject has to be genetically changed at least one of RET.In one embodiment, at least one heredity in RET Change is Gene Fusion or activation point mutation.In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B- RET, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In one embodiment, The activation point mutation is M918T point mutation.In one embodiment, the Gene Fusion is NCOA4-RET fusion.One In a embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET Fusion.In one embodiment, the Gene Fusion is EML4-RET fusion.In one embodiment, the gene melts Conjunction is PARD3-RET fusion.In one embodiment, the Gene Fusion is CLIP1-RET fusion.In an embodiment In, any method as described herein is provided, wherein the cancer in the subject is selected from colorectal cancer, lung cancer, non- Small Cell Lung Cancer, thyroid cancer and medullary carcinoma of thyroid gland.In one embodiment, the cancer in the subject is knot The intestines carcinoma of the rectum.In one embodiment, the colorectal cancer is metastatic colorectal cancer.In one embodiment, The cancer in the subject is lung cancer.In one embodiment, the cancer in the subject is non-small thin Born of the same parents' lung cancer.In one embodiment, the cancer in the subject is thyroid cancer.In one embodiment, institute The cancer stated in subject is medullary carcinoma of thyroid gland.In one embodiment, the cancer in the subject is Solid tumor or liquid tumors.In one embodiment, the cancer in the subject is solid tumor.In an embodiment party In case, the cancer in the subject is liquid tumors.In some embodiments, the subject suffers from RET Lung cancer at least one genetic change, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET The Gene Fusion of fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.Some In embodiment, the subject is with the lung cancer in RET at least one genetic change, wherein at least one something lost Passing change is CCDC6-RET fusion.In some embodiments, the subject suffers from has at least one heredity in RET The lung cancer of change, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, the subject With the lung cancer in RET at least one genetic change, wherein at least one be genetically changed is that PARD3-RET melts It closes.In some embodiments, the subject is with the lung cancer in RET at least one genetic change, wherein described It is CLIP1-RET fusion that at least one, which is genetically changed,.In some embodiments, the subject suffers from has extremely in RET The colorectal cancer of few a kind of genetic change, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET The Gene Fusion of fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.Some In embodiment, the subject in RET with the colorectal cancer that at least one is genetically changed, wherein it is described at least A kind of be genetically changed is CCDC6-RET fusion.In some embodiments, the subject suffers from has at least one in RET The colorectal cancer that kind is genetically changed, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments In, the subject is with the colorectal cancer in RET at least one genetic change, wherein at least one heredity Change is PARD3-RET fusion.In some embodiments, the subject suffers from, and there is at least one heredity to change in RET The colorectal cancer of change, wherein at least one be genetically changed is CLIP1-RET fusion.In some embodiments, described Subject is with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one genetic change Be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and The Gene Fusion of CLIP1-RET fusion.In some embodiments, the subject suffers from has at least one lose in RET The medullary carcinoma of thyroid gland changed is passed, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments In, the subject is with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one something lost Passing change is EML4-RET fusion.In some embodiments, the subject suffers from, and there is at least one heredity to change in RET The medullary carcinoma of thyroid gland of change, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, institute Subject is stated with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one heredity changes Change is CLIP1-RET fusion.In some embodiments, the subject suffers from has at least one be genetically changed in RET Sarcoma, wherein it is described it is at least one be genetically changed be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, The Gene Fusion of EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, described tested Person is with the sarcoma in RET at least one genetic change, wherein at least one be genetically changed is that CCDC6-RET melts It closes.In some embodiments, the subject is with the sarcoma in RET at least one genetic change, wherein described It is EML4-RET fusion that at least one, which is genetically changed,.In some embodiments, the subject suffers from has at least in RET A kind of sarcoma of genetic change, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, The subject is with the sarcoma in RET at least one genetic change, wherein at least one be genetically changed is CLIP1-RET fusion.
There is disclosed herein treatment subject in cancer method comprising (a) obtain the subject one kind or The existing knowledge that at least one of RET in various kinds of cell is genetically changed；(b) therapeutically effective amount is applied to the subject N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-)- 3- isoxazolyl]-urea or its pharmaceutically acceptable salt.In one embodiment, at least one heredity in RET changes Change is Gene Fusion or activation point mutation.In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B- RET, CCDC6-RET fusion, EML4-RET fusion and PARD3-RET fusion.In one embodiment, the activation point mutation It is M918T point mutation.In one embodiment, the Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In a reality It applies in scheme, the Gene Fusion is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET Fusion.
There is disclosed herein the methods of the treating cancer in subject, including applying therapeutically effective amount to the subject N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt, wherein in application N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygen] Phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt it Before, wherein the subject has been diagnosed as with the cancer being genetically changed comprising at least one of RET.In some embodiments In, at least one of RET genetic change is Gene Fusion or activation point mutation.In one embodiment, the gene melts It closes selected from NCOA4-RET, KIF5B-RET, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET Fusion.In one embodiment, at least one be genetically changed in RET is Gene Fusion or activation point mutation.One In a embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B-RET, CCDC6-RET fusion, EML4-RET is merged, PARD3-RET fusion and CLIP1-RET fusion.In one embodiment, the activation point mutation is M918T point mutation.? In one embodiment, the Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B- RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In one embodiment, the base Because fusion is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET fusion.Implement at one In scheme, the Gene Fusion is CLIP1-RET fusion.In one embodiment, any method as described herein is provided, Wherein the cancer in the subject is selected from colorectal cancer, lung cancer, non-small cell lung cancer, thyroid cancer and medullary thyroid Sample cancer.In one embodiment, the cancer in the subject is colorectal cancer.In one embodiment, institute Stating colorectal cancer is metastatic colorectal cancer.In one embodiment, the cancer in the subject is lung cancer. In one embodiment, the cancer in the subject is non-small cell lung cancer.In one embodiment, it is described by The cancer in examination person is thyroid cancer.In one embodiment, the cancer in the subject is medullary thyroid Sample cancer.In one embodiment, the cancer in the subject is solid tumor or liquid tumors.In an embodiment In, the cancer in the subject is solid tumor.In one embodiment, the cancer in the subject is liquid Body tumour.In some embodiments, the subject suffers from the lung cancer in RET at least one genetic change, wherein It is described it is at least one be genetically changed be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, The Gene Fusion of PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, the subject suffers from RET Lung cancer at least one genetic change, wherein at least one be genetically changed is CCDC6-RET fusion.In some implementations In scheme, the subject is with the lung cancer in RET at least one genetic change, wherein at least one heredity changes Change is EML4-RET fusion.In some embodiments, the subject suffers from has at least one genetic change in RET Lung cancer, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, the subject suffers from With the lung cancer of at least one genetic change in RET, wherein at least one be genetically changed is CLIP1-RET fusion.? In some embodiments, the subject is with the colorectal cancer in RET at least one genetic change, wherein described At least one be genetically changed be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, The Gene Fusion of PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, the subject suffers from RET With the colorectal cancer that at least one is genetically changed, wherein at least one be genetically changed is CCDC6-RET fusion.One In a little embodiments, the subject in RET with the colorectal cancer of at least one genetic change, wherein it is described extremely A kind of few genetic change is EML4-RET fusion.In some embodiments, the subject suffers from has at least one in RET The colorectal cancer that kind is genetically changed, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments In, the subject is with the colorectal cancer in RET at least one genetic change, wherein at least one heredity Change is CLIP1-RET fusion.In some embodiments, the subject suffers from, and there is at least one heredity to change in RET The medullary carcinoma of thyroid gland of change, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET fusion, CCDC6- The Gene Fusion of RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, The subject is with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one heredity Change is CCDC6-RET fusion.In some embodiments, the subject suffers from, and there is at least one heredity to change in RET The medullary carcinoma of thyroid gland of change, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, described Subject is with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one genetic change It is PARD3-RET fusion.In some embodiments, the subject suffers from has at least one genetic change in RET Medullary carcinoma of thyroid gland, wherein at least one be genetically changed is CLIP1-RET fusion.In some embodiments, it is described by Examination person is with the sarcoma in RET at least one genetic change, wherein at least one be genetically changed is to be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET melt The Gene Fusion of conjunction.In some embodiments, the subject is with the meat in RET at least one genetic change Tumor, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments, the subject suffers from With the sarcoma of at least one genetic change in RET, wherein at least one be genetically changed is EML4-RET fusion.Some In embodiment, the subject is with the sarcoma in RET at least one genetic change, wherein at least one something lost Passing change is PARD3-RET fusion.In some embodiments, the subject suffers from has at least one heredity in RET The sarcoma of change, wherein at least one be genetically changed is CLIP1-RET fusion.
There is disclosed herein the methods of the treating cancer in subject, including applying therapeutically effective amount to the subject N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt, wherein in application N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygen] Phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt it Before, wherein the subject has previously been diagnosed as with the cancer being genetically changed comprising at least one of RET.In some implementations In scheme, at least one of RET genetic change is Gene Fusion or activation point mutation.In one embodiment, the base Because fusion selected from NCOA4-RET, KIF5B-RET, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In one embodiment, at least one be genetically changed in RET is Gene Fusion or activation point Mutation.In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B-RET, CCDC6-RET fusion, EML4- RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In one embodiment, the activation point mutation is M918T point Mutation.In one embodiment, the Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In one embodiment, The Gene Fusion is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET fusion.One In a embodiment, the Gene Fusion is CLIP1-RET fusion.In one embodiment, as described herein is provided Where method, wherein the cancer in the subject be selected from colorectal cancer, lung cancer, non-small cell lung cancer, thyroid cancer and Medullary carcinoma of thyroid gland.In one embodiment, the cancer in the subject is colorectal cancer.In an embodiment party In case, the colorectal cancer is metastatic colorectal cancer.In one embodiment, the cancer in the subject It is lung cancer.In one embodiment, the cancer in the subject is non-small cell lung cancer.In an embodiment In, the cancer in the subject is thyroid cancer.In one embodiment, the cancer in the subject is Medullary carcinoma of thyroid gland.In one embodiment, the cancer in the subject is solid tumor or liquid tumors.At one In embodiment, the cancer in the subject is solid tumor.In one embodiment, described in the subject Cancer is liquid tumors.In some embodiments, the subject is with the lung in RET at least one genetic change Cancer, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4- The Gene Fusion of RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, the subject suffers from There is the lung cancer in RET at least one genetic change, wherein at least one be genetically changed is CCDC6-RET fusion. In some embodiments, the subject in RET with the lung cancer of at least one genetic change, wherein it is described at least A kind of be genetically changed is EML4-RET fusion.In some embodiments, the subject suffers from has at least one in RET The lung cancer of genetic change, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, described Subject is with the lung cancer in RET at least one genetic change, wherein at least one be genetically changed is CLIP1- RET fusion.In some embodiments, the subject is with the colorectum in RET at least one genetic change Cancer, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4- The Gene Fusion of RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, the subject suffers from There is the colorectal cancer being genetically changed in RET at least one, wherein at least one be genetically changed is CCDC6-RET Fusion.In some embodiments, the subject suffers from the colorectal cancer in RET at least one genetic change, Wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, the subject suffers from RET Colorectal cancer at least one genetic change, wherein at least one be genetically changed is PARD3-RET fusion.One In a little embodiments, the subject in RET with the colorectal cancer of at least one genetic change, wherein it is described extremely A kind of few genetic change is CLIP1-RET fusion.In some embodiments, the subject suffers from has at least in RET A kind of medullary carcinoma of thyroid gland of genetic change, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET The Gene Fusion of fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.Some In embodiment, the subject in RET with the medullary carcinoma of thyroid gland of at least one genetic change, wherein it is described extremely A kind of few genetic change is CCDC6-RET fusion.In some embodiments, the subject suffers from has at least in RET A kind of medullary carcinoma of thyroid gland of genetic change, wherein at least one be genetically changed is EML4-RET fusion.In some implementations In scheme, the subject is with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein described at least one It is PARD3-RET fusion that kind, which is genetically changed,.In some embodiments, the subject suffers from has at least one in RET The medullary carcinoma of thyroid gland of genetic change, wherein at least one be genetically changed is CLIP1-RET fusion.In some embodiments In, the subject is with the sarcoma in RET at least one genetic change, wherein at least one be genetically changed is Selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1- The Gene Fusion of RET fusion.In some embodiments, the subject suffers from has at least one be genetically changed in RET Sarcoma, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments, the subject suffers from There is the sarcoma in RET at least one genetic change, wherein at least one be genetically changed is EML4-RET fusion.? In some embodiments, the subject is with the sarcoma in RET at least one genetic change, wherein described at least one It is PARD3-RET fusion that kind, which is genetically changed,.In some embodiments, the subject suffers from has at least one in RET The sarcoma of genetic change, wherein at least one be genetically changed is CLIP1-RET fusion.
There is disclosed herein pharmaceutical compositions, and it includes N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygen] phenyl]- N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt and it is a kind of or A variety of chemotherapeutants or radiotherapy combine, and such as usually application with treating cancer, the symptom of improvement cancer or prevention or delays The radiotherapy of the breaking-out of cancer.This kind of medicament may include but be not limited to antihormone agent (such as antiestrogenic, antiandrogen and fragrance Enzyme inhibitor), topoisomerase I inhibitor, Topoisomerase II inhibitors, target micro-pipe reagent, platinum based chemotherapy, alkanisation Agent, DNA damage or intercalator, antineoplastic, antimetabolite, other kinase inhibitors, other anti-angiogenic agents, driving albumen Inhibitor, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, farnesyl transferase inhibitor With anoxic response inhibitor.
There is disclosed herein a kind of product or kits, and it includes N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygen] Phenyl]-N'- [5- (2,2,2- tri- fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or Its pharmaceutical composition and one or more chemotherapeutants, as simultaneously, separately or sequentially being used in anti-cancer therapies Combination prepared product.There is disclosed herein a kind of product or kit, it includes for N- [3- [(6,7- dimethoxy-4 's-quinoline azoles Quinoline base) oxygen] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea compound or its medicine Acceptable salt or its pharmaceutical composition and one or more chemotherapeutants on, as same in anti-cancer therapies When, the combination prepared product that separately or successively uses.
There is disclosed herein N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl] purposes of-urea or its pharmaceutically acceptable salt as drug.In a reality It applies in scheme, the drug is intended for the subject with cancer.In one embodiment, it is known that in the subject The cancer has at least one be genetically changed in RET.In one embodiment, at least one heredity in RET Change is Gene Fusion or activation point mutation.In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B- RET, CCDC6-RET fusion, EML4-RET fusion and PARD3-RET fusion.In one embodiment, the activation point mutation It is M918T point mutation.In one embodiment, the Gene Fusion is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In a reality It applies in scheme, the Gene Fusion is EML4-RET fusion.In one embodiment, the Gene Fusion is PARD3-RET Fusion.
There is disclosed herein N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl] purposes of-urea or its pharmaceutically acceptable salt as drug.In a reality It applies in scheme, the drug is intended for the subject with cancer.In one embodiment, it is known that in the subject The cancer has at least one be genetically changed in RET.In one embodiment, at least one heredity in RET Change is Gene Fusion or activation point mutation.In one embodiment, the Gene Fusion is selected from NCOA4-RET, KIF5B- RET, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In one embodiment, The activation point mutation is M918T point mutation.In one embodiment, the Gene Fusion is NCOA4-RET fusion.One In a embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET Fusion.In one embodiment, the Gene Fusion is EML4-RET fusion.In one embodiment, the gene melts Conjunction is PARD3-RET fusion.In one embodiment, the Gene Fusion is CLIP1-RET fusion.In an embodiment In, any method as described herein is provided, wherein the cancer in the subject is selected from colorectal cancer, lung cancer, non- Small Cell Lung Cancer, thyroid cancer and medullary carcinoma of thyroid gland.In one embodiment, the cancer in the subject is knot The intestines carcinoma of the rectum.In one embodiment, the colorectal cancer is metastatic colorectal cancer.In one embodiment, The cancer in the subject is lung cancer.In one embodiment, the cancer in the subject is non-small thin Born of the same parents' lung cancer.In one embodiment, the cancer in the subject is thyroid cancer.In one embodiment, institute The cancer stated in subject is medullary carcinoma of thyroid gland.In one embodiment, the cancer in the subject is Solid tumor or liquid tumors.In one embodiment, the cancer in the subject is solid tumor.In an embodiment party In case, the cancer in the subject is liquid tumors.In some embodiments, the subject suffers from RET Lung cancer at least one genetic change, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET The Gene Fusion of fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.Some In embodiment, the subject is with the lung cancer in RET at least one genetic change, wherein at least one something lost Passing change is CCDC6-RET fusion.In some embodiments, the subject suffers from has at least one heredity in RET The lung cancer of change, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, the subject With the lung cancer in RET at least one genetic change, wherein at least one be genetically changed is that PARD3-RET melts It closes.In some embodiments, the subject is with the lung cancer in RET at least one genetic change, wherein described It is CLIP1-RET fusion that at least one, which is genetically changed,.In some embodiments, the subject suffers from has extremely in RET The colorectal cancer of few a kind of genetic change, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET The Gene Fusion of fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.Some In embodiment, the subject in RET with the colorectal cancer that at least one is genetically changed, wherein it is described at least A kind of be genetically changed is CCDC6-RET fusion.In some embodiments, the subject suffers from has at least one in RET The colorectal cancer that kind is genetically changed, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments In, the subject is with the colorectal cancer in RET at least one genetic change, wherein at least one heredity Change is PARD3-RET fusion.In some embodiments, the subject suffers from, and there is at least one heredity to change in RET The colorectal cancer of change, wherein at least one be genetically changed is CLIP1-RET fusion.In some embodiments, described Subject is with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one genetic change Be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and The Gene Fusion of CLIP1-RET fusion.In some embodiments, the subject suffers from has at least one lose in RET The medullary carcinoma of thyroid gland changed is passed, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments In, the subject is with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one something lost Passing change is EML4-RET fusion.In some embodiments, the subject suffers from, and there is at least one heredity to change in RET The medullary carcinoma of thyroid gland of change, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, institute Subject is stated with the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one heredity changes Change is CLIP1-RET fusion.In some embodiments, the subject suffers from has at least one be genetically changed in RET Sarcoma, wherein it is described it is at least one be genetically changed be selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, The Gene Fusion of EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, described tested Person is with the sarcoma in RET at least one genetic change, wherein at least one be genetically changed is that CCDC6-RET melts It closes.In some embodiments, the subject is with the sarcoma in RET at least one genetic change, wherein described It is EML4-RET fusion that at least one, which is genetically changed,.In some embodiments, the subject suffers from has at least in RET A kind of sarcoma of genetic change, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, The subject is with the sarcoma in RET at least one genetic change, wherein at least one be genetically changed is CLIP1-RET fusion.
There is disclosed herein N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be used to prepare it is with anti-tumor activity The purposes of drug.In one embodiment, the drug is intended for the subject with cancer.In an embodiment In, it is known that the cancer in the subject has at least one be genetically changed in RET.In one embodiment, RET In at least one be genetically changed be Gene Fusion or activation point mutation.In one embodiment, the Gene Fusion Selected from NCOA4-RET, KIF5B-RET, CCDC6-RET fusion, EML4-RET fusion and PARD3-RET fusion.Implement at one In scheme, the activation point mutation is M918T point mutation.In one embodiment, the Gene Fusion is that NCOA4-RET melts It closes.In one embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, the Gene Fusion is CCDC6-RET fusion.In one embodiment, the Gene Fusion is EML4-RET fusion.In one embodiment, institute Stating Gene Fusion is PARD3-RET fusion.
There is disclosed herein N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be used to prepare it is with anti-tumor activity The purposes of drug.In one embodiment, the drug is intended for the subject with cancer.In an embodiment In, it is known that the cancer in the subject has at least one be genetically changed in RET.In one embodiment, RET In at least one be genetically changed be Gene Fusion or activation point mutation.In one embodiment, the Gene Fusion Melt selected from NCOA4-RET, KIF5B-RET, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET It closes.In one embodiment, the activation point mutation is M918T point mutation.In one embodiment, the Gene Fusion It is NCOA4-RET fusion.In one embodiment, Gene Fusion is KIF5B-RET fusion.In one embodiment, institute Stating Gene Fusion is CCDC6-RET fusion.In one embodiment, the Gene Fusion is EML4-RET fusion.At one In embodiment, the Gene Fusion is PARD3-RET fusion.In one embodiment, the Gene Fusion is CLIP1- RET fusion.In one embodiment, any method as described herein is provided, wherein the cancer in the subject Selected from colorectal cancer, lung cancer, non-small cell lung cancer, thyroid cancer and medullary carcinoma of thyroid gland.In one embodiment, described The cancer in subject is colorectal cancer.In one embodiment, the colorectal cancer is that metastatic colon is straight Intestinal cancer.In one embodiment, the cancer in the subject is lung cancer.In one embodiment, described tested The cancer in person is non-small cell lung cancer.In one embodiment, the cancer in the subject is thyroid gland Cancer.In one embodiment, the cancer in the subject is medullary carcinoma of thyroid gland.In one embodiment, institute Stating the cancer in subject is solid tumor or liquid tumors.In one embodiment, the cancer in the subject Disease is solid tumor.In one embodiment, the cancer in the subject is liquid tumors.In some embodiments In, the subject is with the lung cancer in RET at least one genetic change, wherein at least one be genetically changed is Selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1- The Gene Fusion of RET fusion.In some embodiments, the subject suffers from has at least one be genetically changed in RET Lung cancer, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments, the subject suffers from There is the lung cancer in RET at least one genetic change, wherein at least one be genetically changed is EML4-RET fusion.? In some embodiments, the subject is with the lung cancer in RET at least one genetic change, wherein described at least one It is PARD3-RET fusion that kind, which is genetically changed,.In some embodiments, the subject suffers from has at least one in RET The lung cancer of genetic change, wherein at least one be genetically changed is CLIP1-RET fusion.In some embodiments, described Subject is with the colorectal cancer in RET at least one genetic change, wherein at least one be genetically changed is Selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1- The Gene Fusion of RET fusion.In some embodiments, the subject suffers from has at least one genetic change in RET Colorectal cancer, wherein at least one be genetically changed is CCDC6-RET fusion.In some embodiments, it is described by Examination person is with the colorectal cancer in RET at least one genetic change, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, the subject is with the colon in RET at least one genetic change The carcinoma of the rectum, wherein at least one be genetically changed is PARD3-RET fusion.In some embodiments, the subject suffers from There is the colorectal cancer in RET at least one genetic change, wherein at least one be genetically changed is CLIP1-RET Fusion.In some embodiments, the subject is with the medullary thyroid sample in RET at least one genetic change Cancer, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B-RET fusion, CCDC6-RET fusion, EML4- The Gene Fusion of RET fusion, PARD3-RET fusion and CLIP1-RET fusion.In some embodiments, the subject suffers from There is the medullary carcinoma of thyroid gland in RET at least one genetic change, wherein at least one be genetically changed is CCDC6- RET fusion.In some embodiments, the subject is with the medullary thyroid in RET at least one genetic change Sample cancer, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, the subject suffers from With the medullary carcinoma of thyroid gland of at least one genetic change in RET, wherein at least one be genetically changed is that PARD3-RET melts It closes.In some embodiments, the subject suffers from the medullary carcinoma of thyroid gland in RET at least one genetic change, Wherein at least one be genetically changed is CLIP1-RET fusion.In some embodiments, the subject suffers from RET In the sarcoma at least one genetic change, wherein at least one be genetically changed is selected from NCOA4-RET, KIF5B- The Gene Fusion of RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion.? In some embodiments, the subject is with the sarcoma in RET at least one genetic change, wherein described at least one It is CCDC6-RET fusion that kind, which is genetically changed,.In some embodiments, the subject suffers from has at least one in RET The sarcoma of genetic change, wherein at least one be genetically changed is EML4-RET fusion.In some embodiments, it is described by Examination person is with the sarcoma in RET at least one genetic change, wherein at least one be genetically changed is PARD3-RET Fusion.In some embodiments, the subject suffers from the sarcoma in RET at least one genetic change, wherein institute Stating at least one be genetically changed is CLIP1-RET fusion.
There is disclosed herein N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be for the use in the method for the treatment of cancer On the way.Some embodiments can further be summarized by reference to the embodiment that number set forth below is listed:
1. a kind for the treatment of cancer, the symptom for improving cancer, the method for delaying the breaking-out of cancer or delaying the progress of cancer, packet Containing following steps:
Determine whether the active adjusting of RET is defective in the cell mass of subject, and if the active adjusting of the RET It is defective,
To the subject apply N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2, The fluoro- 1,1- dimethyl ethyl of 2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt.
To treat subject cancer, improve subject cancer symptom, delay subject cancer breaking-out or Delay the progress of the cancer of subject.
2. method described in embodiment 1, wherein the determining RET it is active adjust it is whether defective be included in it is described by RET kinase activity is measured in the extract of the cell mass of examination person.
3. method described in embodiment 1, wherein the determining RET it is active adjust it is whether defective be included in it is described by Transcript accumulation is measured in the extract comprising RNA of the cell mass of examination person.
4. method described in embodiment 1, wherein active whether defective adjust of the determining RET includes to described RET locus sequencing in the genomic DNA of the cell mass of subject.
5. method described in embodiment 4, wherein it includes the active up-regulation of RET that the active defect of the RET, which is adjusted,.
6. method described in embodiment 5, wherein the fusion in the code area of second of protein of the RET locus Indicate the up-regulation of RET kinase activity.
7. method described in embodiment 4, wherein the active defect of the RET adjust include RET activity be reduced to it is lower It is horizontal.
8. method described in embodiment 7, wherein the null mutation instruction RET activity of the RET locus reduces.
9. method described in embodiment 7, wherein the null mutation includes insertion.
10. method described in embodiment 7, wherein the null mutation includes the frameshit for encoding the code area of RET.
11. method described in embodiment 7, wherein the null mutation includes the missing in the locus for encode RET.
12. method described in embodiment 7, wherein the null mutation includes across the nucleic acid sequence of RET locus Missing.
13. method described in embodiment 7, wherein the mutation for influencing the accumulation of RET mRNA shows the reduction of RET activity.
Some embodiments include any of methods described herein, wherein N- [3- [(6,7- dimethoxy-4 's-quinazoline Base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt received is with about 200mg/m2To about 1600mg/m2Amount be applied to the subject, or about 200mg/m2To about 1200mg/m2, Or about 200mg/m2To about 1000mg/m2, or about 400mg/m2To about 1200mg/m2, or about 400mg/m2To about 1000mg/m2, Or about 800mg/m2To about 1000mg/m2, or about 800mg/m2To about 1200mg/m2, or about 800mg/m2To about 1200mg/m2, Or about 800mg/m2To about 1600mg/m2.Some embodiments include any of methods described herein, wherein N- [3- [(6,7- Dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl] - Urea or its pharmaceutically acceptable salt are with about 200mg/m2, about 300mg/m2, about 400mg/m2、500mg/m2, about 600mg/m2, about 700mg/m2, about 800mg/m2, about 900mg/m2, about 1000mg/m2, about 1100mg/m2, about 1200mg/m2, about 1300mg/m2、 About 1400mg/m2, about 1500mg/m2, about 1600mg/m2, about 1700mg/m2, about 1800mg/m2, about 1900mg/m2Or about 2000mg/m2Amount be applied to the subject.
Some embodiments are related to comprising N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt composition.Therefore, In some embodiments, the present invention relates to include N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt can pharmaceutically connect The pharmaceutical composition of the carrier and optionally at least one other drugs or medicament received.In some embodiments, at least one The anticancer agent that kind other drug or medicament are discussed further below.
Pharmaceutically acceptable carrier may include conventional pharmaceutical carrier or excipient.Suitable pharmaceutical carrier includes lazy Property diluent or filler, water and various organic solvents (such as hydrate and solvate).If desired, pharmaceutical composition can contain There are supplementary element, such as flavoring agent, binder, excipient.Therefore, for oral administration, contain various excipient such as citric acid Tablet can with various disintegrating agents (such as starch, alginic acid and certain composition silicates) and bonding reagent (such as sucrose, gelatin and Ah Draw primary glue) it is used together.In addition, lubricant such as magnesium stearate, lauryl sodium sulfate and talcum are generally used for film-making purpose. The solid composite of similar type can also be used in the gelatine capsule of soft and hard filling.Therefore, the non-limiting example packet of material Include lactose or toffee and high molecular weight polyethylene glycol.When it is expected aqueous suspension or elixir for oral administration, work therein Property compound can be with various sweeteners or flavoring agent, colorant or dye combinations, and if desired, can also be with emulsifier or outstanding Floating agent and diluent (such as water, ethyl alcohol, propylene glycol, glycerol or combinations thereof) combination.
Pharmaceutical composition may, for example, be the tablet for being suitable for oral administration, capsule, pill, powder, extended release preparation, The form of solution suspension is suitable for the sterile solution, suspension or emulsion form of parenteral injection, is suitable for local application The form of ointment or emulsifiable paste, or it is suitable for the suppository form of rectal administration.
Exemplary parenteral administration form includes the suspension of the reactive compound in solution or sterile aqueous solution, example Such as, propylene glycol aqueous solution or glucose aqueous solution.If desired, this kind of dosage form can be buffered suitably.
Pharmaceutical composition can be suitable for the unit dosage forms of the single administration of exact dose.
In some embodiments, composition includes the compound as disclosed herein of therapeutically effective amount and pharmaceutically may be used The carrier of receiving.
The compound of the present invention can be approved that suitable any medicament forms are deployed into medicine as described below with technical staff Compositions.Pharmaceutical composition of the invention includes at least one compound disclosed herein and inert medicine of therapeutically effective amount The upper acceptable carrier of object or diluent.
To treat or prevent by the RET disease mediated or the patient's condition, pharmaceutical composition of the invention is applied with suitable preparation With the preparation passes through the N- that effective quantity (that is, RET modulation, adjusting or amount of suppression for effectively realizing therapeutic effect) is treated in combination [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt (as active constituent) and one or more pharmaceutically suitable carriers Prepare, the carrier can be selected from the diluent for for example promoting reactive compound to be processed into final pharmaceutical preparations, excipient and Auxiliary agent.
The pharmaceutical carrier of use can be solid or liquid.Exemplary of solid carriers is lactose, sucrose, talcum, gelatin, fine jade Rouge, pectin, Arabic gum, magnesium stearate, stearic acid etc..Exemplary liquid carriers are syrup, peanut oil, olive oil, water etc..Class As, composition of the invention may include delay known in the art or time releasable material, such as individual glycerol monostearate Ester or distearin or with wax, ethyl cellulose, hydroxypropyl methyl cellulose, methyl methacrylate etc. together.It can Other additive or excipient are added to realize desired formulation properties.For example, bioavilability reinforcing agent can be added (such as Labrasol, Gelucire) or blender, such as CMC (carboxymethyl cellulose), PG (propylene glycol) or PEG (poly- second two Alcohol).Such as it can be added when preparing capsule preparationsA kind of protection activity ingredient is made from light, moisture and oxidation Semisolid mediator.
If preparation can be tablet using solid carrier, it is put into in powder or the hard gelatin capsule of pellet form, Or be formed as sugar-coat ingot or pastille.The amount of solid carrier is alterable, but will usually be about 25mg to about 1g.If carried using liquid Body, then composite can be sterile injectable solution in syrup, lotion, Perle, ampoule or bottle or suspension or The form of non-aqueous liquid suspension.If composite can be hard and soft-gelatin capsule formulation using semi-solid carrier Form.Composition of the invention is prepared with the unit dosage forms for being suitable for method of application (such as parenteral or oral administration).
It, can be by N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] benzene in order to obtain stable water-soluble dosage forms Base] salt of-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea is dissolved in organic or inorganic acid In aqueous solution, in 0.3M succinic acid or citric acid solution.If soluble-salt form cannot be obtained, medicament dissolution can be existed In the combination of suitable cosolvent or cosolvent.The example of suitable cosolvent includes alcohol, propylene glycol, Liquid Macrogol, poly- mountain Pears alcohol ester 80, glycerol etc., concentration range are the 0% to 60% of total volume.In an exemplary embodiment, by N- [3- [(6, 7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazole Base]-urea or its pharmaceutically acceptable salt is dissolved in DMSO and is diluted with water.Composition can also be the activity of salt form Solution form of the ingredient in aqueous mediator (such as water or isotonic saline solution or dextrose solution) appropriate.
Preparation appropriate depends on selected administration method.It, can be by N- [3- [(6,7- dimethoxy-4 's-for injection Quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its drug Preferably in the buffer of physical compatibility, (such as Hanks solution, Ringer's solution or physiological saline are slow for acceptable salt on Fliud flushing) in be deployed into aqueous solution.For transmucosal or transdermal administration, in the formulation using the infiltration for the barrier for being suitable for permeate Agent.This bleeding agent is generally known in the art.
For oral administration, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- Three fluoro- 1,1- dimethyl ethyls) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt can be by by reactive compound It combines and prepares with pharmaceutically acceptable carrier known in the art.These carriers enable the compound of the present invention to match Tablet, pill, dragee, capsule, liquid, gel, syrup, slurries, suspension etc. is made, is taken orally for subject to be treated Intake.The pharmaceutical preparation being administered orally can be used solid excipient and mix with active constituent (medicament), optionally grinding gained Mixture, and if desired, adding suitable auxiliary agent post-processing granulate mixture, to obtain tablet or Dragee cores. Suitable excipient includes: filler, such as sugar including lactose, sucrose, mannitol or D-sorbite；With cellulose preparation, Such as cornstarch, wheaten starch, rice starch, potato starch, gelatin, natural gum, methylcellulose, hydroxypropyl methyl are fine Dimension element, sodium carboxymethylcellulose or polyvinylpyrrolidone (PVP).If desired, disintegrating agent can be added, such as crosslinking is poly- Vinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.
Dragee core is provided with suitable coating.For this purpose, concentrated sugar solution can be used, can optionally contain There are gum arabic, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol and/or titanium dioxide, paint solution and suitable Organic solvent or solvent mixture.Dyestuff or pigment can be added in tablet or dragee coatings to be used to identify or characterize The various combination of activating agent.
The pharmaceutical preparation that can be administered orally include capsule is pushed and fitted made of gelatin, and made of gelatin it is soft Seal capsule and plasticizer, such as glycerol or D-sorbite.Push-in type capsule can be containing active constituent and filler (such as lactose), viscous The mixture of mixture (such as starch) and/or lubricant (such as talcum powder or magnesium stearate) and optional stabilizer.In soft capsule, Activating agent can be dissolved or suspended in suitable liquid, such as fat oil, atoleine or liquid macrogol.In addition, can To add stabilizer.All formulations for oral administration are suitable for this applied dose described in answering.For oral administration, Composition can be using the form for the tablet or pastille prepared in a usual manner.
For being applied through intranasal administration or by sucking, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] benzene Base]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt can By easily from the aerosol spray presentation of pressurized package or sprayer in the form of deliver, use suitable propellant, such as two Dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide or other suitable gases.In the feelings of pressurised aerosol Under condition, dosage unit can be determined by providing the valve of delivering metered amount.It can be formulated for inhalator or insufflator etc. Gelatine capsule and cylindrantherae, the mixture of powders containing compound and suitable powdered substrate such as lactose or starch.
N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (fluoro- 1,1- diformazan of 2,2,2- tri- Base ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt can be configured to for by injection, such as parenteral Application, passes through bolus injection or continuous infusion.Preparation for injection can exist in a unit, for example, in ampoule or In multi-dose container, there is the preservative of addition.The composition can take the suspension in such as oiliness or aqueous carrier, The form of solution or lotion, and preparaton can be contained, such as suspending agent, stabilizer and/or dispersing agent.
Pharmaceutical preparation for parenteral administration includes the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) of water-soluble form Oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its be pharmaceutically subjected to Salt.In addition, the suspension of activating agent can be prepared into oily injection suspensions appropriate.Suitable lipophilic solvent or carrier Including fat oil, such as sesame oil or Acrawax, such as ethyl oleate or triglycerides or liposome.Aqueous inj ection is outstanding Supernatant liquid contains the substance for increasing suspension viscosity, such as sodium carboxymethylcellulose, D-sorbite or glucan.Optionally, it hangs The supernatant liquid also reagent containing suitable stabilizer or increase compound solubility, to prepare highly concentrated solution.
Alternatively, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, 1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt can be powder type, for it is suitable Carrier, such as sterile pyrogen-free water, before the use.
In addition to formulations described above, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt can also prepare growth Imitate preparation.This durative action preparation can be applied by implantation (for example, subcutaneous or intramuscular) or by intramuscular injection.Therefore, example Such as, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1,1- dimethyl second Base) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt can use suitable polymerization or hydrophobic material (for example, as It is acceptable oil in lotion) ion exchange resin or as sparing soluble derivative prepare, for example, as slightly soluble salt.For dredging The pharmaceutical carrier of aqueous compounds is co-solvent system, and it includes benzyl alcohol, non-polar surfactant, water miscibility are organic poly- Close object and water phase.Co-solvent system can be VPD co-solvent system.VPD is 3%w/v benzyl alcohol, and 8%w/v apolar surfaces are living The solution of property agent polysorbate80 and 65%w/v Liquid Macrogol, by volume in dehydrated alcohol.VPD co-solvent system (VPD:5W) containing with the diluted VPD of 1:1 and 5% glucose solution.The co-solvent system dissolves hydrophobicity well Object is closed, and itself generates hypotoxicity in systemic administration.The ratio of cosolvent system can be suitably changed without destroying it Solubility and toxic characteristic.In addition, the characteristic of cosolvent component can change: it is, for example, possible to use other low-toxicity nonpolars Surfactant replaces polysorbate80；The score size of polyethylene glycol can change；Other biocompatible polymers can Instead of polyethylene glycol, such as polyvinylpyrrolidone；It can replace dextrose with other sugar or polysaccharide.
Alternatively, other delivery systems of hydrophobic pharmaceutical compounds can be used.Liposome and emulsion are to use In the delivery vector of hydrophobic drug or the known embodiment of carrier.Also certain organic solvents, such as dimethyl sulfoxide can be used, But due to the toxicity of DMSO, usually using bigger toxicity as cost.Further, it is possible to use sustained release system delivers compound, Such as the semipermeable matrices of the solid hydrophobic polymers containing therapeutic agent.It has been set up various slow-release materials and is this field Known to technical staff.According to its chemical property, spansule can discharge compound several weeks to more than 100 days.Depending on controlling The chemical property and biological stability of reagent are treated, other strategies of protein stabilization can be used.
Pharmaceutical composition also may include suitable solid phase or gel phase carriers or excipient.These carriers and excipient can be with Significantly improve the bioavilability of insoluble drug.Examples of such carriers or the example of excipient include calcium carbonate, calcium phosphate, sugar, shallow lake Powder, cellulose derivative, gelatin and polymer such as polyethylene glycol.In addition it is possible to use additive or excipient, such as Deng.
Further, pharmaceutical composition can be integrated into skin patch for directly delivering drug on the skin.
It should be understood that N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- Three fluoro- 1,1- dimethyl ethyls) -3- isoxazolyl] actual dose of-urea or its pharmaceutically acceptable salt will be according to using Concrete medicament, the concrete composition of preparation, administration mode and treated concrete position, host and disease and change.In view of The experimental data of given compound, those skilled in the art can determine the best of specified criteria group using routine dose measurement test Dosage.For being administered orally, usually used exemplary daily dose is about 0.001 to about 1000mg/kg weight, with appropriate Every repetitive treatment process.
Moreover, pharmaceutically acceptable preparation of the invention may include the compound of the present invention or its salt or solvate, In an amount of from about 10mg to about 2000mg, or about 10mg to about 1500mg, or about 10mg to about 1000mg, or about 10mg is to about 750mg, or about 10mg to about 500mg, or about 25mg to about 500mg, or about 50 to about 500mg, or about 100mg to about 500mg. In addition, pharmaceutically acceptable preparation of the invention may include the compound of the present invention or its salt or solvate, amount It is about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg or about 500mg.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt with about 100mg daily Amount to about 1000mg is administered to the subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinoline Oxazoline base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically Acceptable salt is applied to the subject with the amount of about 100mg to about 900mg daily.In one embodiment, the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 100mg to about 800mg be daily applied to the subject.? In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt with about 100mg daily to about 700mg's Amount is applied to the subject.In one embodiment, the N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] Phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt with The amount of daily about 100mg to about 600mg are applied to the subject.In one embodiment, N- [3- [(6, the 7- diformazans Oxygroup -4- quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or Its pharmaceutically acceptable salt is applied to the subject with the amount of about 100mg to about 500mg daily.In an embodiment In, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, the 1- dimethyl Ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be applied to the amount of about 100mg to about 400mg daily it is described Subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt with about 100mg daily extremely The amount of about 375mg is applied to the subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazoline Base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt received is applied to the subject with the amount of about 100mg to about 350mg daily.In one embodiment, the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) different evil of -3- Oxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 150mg to about 1000mg be daily applied to the subject.One In a embodiment, [(2,2,2- tri- is fluoro- by 5- by-N'- for the N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl] 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be with about 175mg daily to the amount of about 1000mg It is applied to the subject.In one embodiment, described N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] benzene Base]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be with every The amount of its about 200mg to about 1000mg are applied to the subject.In one embodiment, N- [3- [(6, the 7- diformazans Oxygroup -4- quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or Its pharmaceutically acceptable salt is applied to the subject with the amount of about 225mg to about 1000mg daily.In an embodiment In, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, the 1- dimethyl Ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be applied to the amount of about 175mg to about 800mg daily it is described Subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt with about 275mg daily extremely The amount of about 350mg is applied to the subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinazoline Base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its can pharmaceutically connect The salt received is applied to the subject with the amount of about 200mg daily.In one embodiment, N- [3- [(6, the 7- diformazans Oxygroup -4- quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or Its pharmaceutically acceptable salt is applied to the subject with the amount of about 225mg daily.In one embodiment, the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 250mg be daily applied to the subject.Implement at one In scheme, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, the 1- bis- Methylethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be applied to the amount of about 275mg daily it is described tested Person.In one embodiment, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] the phenyl]-N'- [5- (2,2, The fluoro- 1,1- dimethyl ethyl of 2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt applied with the amount of about 300mg daily For the subject.In one embodiment, described N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] benzene Base]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be with every The amount of its about 325mg is applied to the subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinoline azoles Quinoline base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically may be used The salt of receiving is applied to the subject with the amount of about 350mg daily.In one embodiment, the N- [3- [(6,7- bis- Methoxyl group -4- quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea Or its pharmaceutically acceptable salt is applied to the subject with the amount of about 375mg daily.In one embodiment, the N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-urea or its pharmaceutically acceptable salt with the amount of about 400mg be daily applied to the subject.Implement at one In scheme, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, the 1- bis- Methylethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be applied to the amount of about 425mg daily it is described tested Person.In one embodiment, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] the phenyl]-N'- [5- (2,2, The fluoro- 1,1- dimethyl ethyl of 2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt applied with the amount of about 450mg daily For the subject.In one embodiment, described N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] benzene Base]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be with every The amount of its about 475mg is applied to the subject.In one embodiment, N- [3- [(6, the 7- dimethoxy-4 's-quinoline azoles Quinoline base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically may be used The salt of receiving is applied to the subject with the amount of about 500mg daily.
In addition, pharmaceutically acceptable preparation of the invention may include N- [3- [(6, the 7- dimethoxy-4 's-of following amounts Quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its drug Acceptable salt on: about 0.5w/w% to about 95w/w% or about 1w/w% to about 95w/w% or about 1w/w% to about 75w/ W% or about 5w/w% are to about 75w/w% or about 10w/w% to about 75w/w% or about 10w/w% to about 50w/w%.
Any of presently disclosed method is also disclosed, wherein by the N- [3- [(6,7- dimethoxy-4 's-quinazoline Base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically may be used The salt of receiving, or comprising N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, 1- dimethyl ethyl) -3- isoxazolyl] pharmaceutical composition of-urea or its pharmaceutically acceptable salt is administered to cancer Subject, individually or as a part of pharmaceutically acceptable preparation, once a day, twice a day, three times a day, or One day four times, in addition it is more frequent.In one embodiment, by N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] benzene Base]-N'- [5- (2,2,2- tri- fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or Include N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl second of 2,2,2- tri- Base) -3- isoxazolyl] pharmaceutical composition of-urea or its pharmaceutically acceptable salt is administered to the subject once a day. In one embodiment, by N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- diformazans Oxygroup -4- quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or The pharmaceutical composition of its pharmaceutically acceptable salt is administered to the subject twice daily.In one embodiment, will N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-)- 3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygen Base] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or it is pharmaceutically acceptable The pharmaceutical composition of salt is administered to the subject three times a day.In one embodiment, by N- [3- [(6,7- dimethoxies Base -4- quinazolyl) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its Pharmaceutically acceptable salt, or comprising N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2, The fluoro- 1,1- dimethyl ethyl of 2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt pharmaceutical composition it is daily It is administered to the subject four times.In one embodiment, by N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] Phenyl]-N'- [5- (2,2,2- tri- fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, Or include N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl of 2,2,2- tri- Ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be administered to for pharmaceutical composition daily five times it is described tested Person.
Any of presently disclosed method is also disclosed, wherein by the N- [3- [(6,7- dimethoxy-4 's-quinazoline Base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically may be used The salt of receiving, or comprising N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, 1- dimethyl ethyl) -3- isoxazolyl] pharmaceutical composition of-urea or its pharmaceutically acceptable salt is administered to cancer Subject, individually or as a part of pharmaceutically acceptable preparation, in the eating state in or in fasting state.? In one embodiment, by N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl], [(2,2,2- tri- is fluoro- by 5- by-N'- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxies Base -4- quinazolyl) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its Pharmaceutically the pharmaceutical composition of acceptable salt in the eating state in be administered to the subject.In one embodiment, By N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl second of 2,2,2- tri- Base) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxy-4 's-quinazoline Base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically may be used The pharmaceutical composition of the salt of receiving is administered to the subject in fasting state.
Ordinarily skilled artisan will understand that relative to N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]- N'- [5- (2,2,2- tri- fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or packet Containing N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl second of 2,2,2- tri- Base) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt pharmaceutical composition, specific pharmaceutical preparation, dosage and every Give within one day that need the dose quantity of the subject of this treatment be all in the knowledge of those of ordinary skill in the art Selection, and can determine without excessive experiment.
N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (fluoro- 1,1- diformazan of 2,2,2- tri- Base ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxy-4 's-quinoline azoles Quinoline base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically The compound can be by that can be delivered to any method of action site by the application of the pharmaceutical composition of acceptable salt Come carry out.These methods include oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intramuscular, Intravascular or infusion), part and rectal administration.
Dosage can be adjusted to provide optimal desired reaction.It, can be with for example, single bolus can be applied Several separated dosage are applied at any time, or dosage can be proportionally reduced or increased according to the urgency level for the treatment of condition. Parenteral composition is prepared with dosage unit form to be particularly advantageous in order to apply with dose uniformity.As used herein, agent Amount unit form refers to the physically discrete unit for the unit dose for being suitable as mammalian subject to be treated；Each list Reactive compound of the position containing predetermined amount, required therapeutic effect can be generated together with required pharmaceutical carrier by being computed.This The specification of the dosage unit form of invention is decided by and directly depends on the specific characteristic of (a) chemotherapeutant and to be realized Particular treatment or preventive effect and (b) are compounded this reactive compound and are used to treat limit intrinsic in the field of subject's sensibility Degree.
Therefore, it will be understood by those skilled in the art that being based on disclosure provided herein, the dosage and application program root It is adjusted according to the method well known to therapy field.That is, can readily determine that maximum tolerable dose, and may be used also The effective quantity of detectable treatment benefit, and every kind of medicament of application are provided to determine to subject to provide and can examine to subject The time requirement of the treatment benefit of survey.Therefore, although certain dosage and application program have been illustrated herein, these embodiments The dosage and application program that can be provided in carrying out the present invention to subject are provided.
It should be noted that dose value can change with the type and severity of situation to be alleviated, and can wrap Include single dose or multi-dose.It is to be further understood that should be needed according to subject for any particular subject and apply or supervise The professional judgement of the people of composition application adjusts particular dosage regimen at any time, and dosage range as described herein is exemplary , and it is not intended to be limited to the range or practice of composition claimed.For example, pharmacokinetics or pharmacodynamics can be based on Parameter adjusts dosage, may include clinical effectiveness, such as toxic effect and/or laboratory evaluation.Therefore, the present invention include by Dosage escalation in the subject that technical staff determines.Determine the suitable dose for applying chemotherapeutant to scheme in related neck It is well known in domain, and introduction disclosed herein is once provided, it will accordingly be understood that being includes range in those skilled in the art It is interior.
It includes but is not limited to cancer below that compound, composition, combination and method provided herein, which can be used for treating: being followed Loop system, such as heart (sarcoma [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, embryonal-cell lipoma, myxoma, rhabdomyoma, fibre Tie up tumor, lipoma and teratoma), mediastinum and pleura and other thoracic organs, hemangioma and tumor-associated vessels tissue；Breathing Road, such as nasal cavity and middle ear, attached sinus, larynx, trachea-bronchial epithelial cell and lung, such as Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), bronchiolar carcinoma (squamous cell, undifferentiated cellule, undifferentiated maxicell, gland cancer), alveolar (bronchiole) cancer, branch Tracheae adenoma, sarcoma, lymthoma, chondroma hamartoma, celiothelioma；Gastronintestinal system, for example, esophagus (squamous cell carcinoma, gland cancer, Leiomyosarcoma, lymthoma), stomach (carcinoma, lymthoma, leiomyosarcoma), stomach, pancreas (duct adenocarcinoma, insulinoma, pancreas Glucagonoma, gastrinoma, carcinoid tumor, vasopressin), small intestine (gland cancer, lymthoma, carcinoid tumor, card wave Ji Shi meat Tumor, liomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (gland cancer, tubular adenoma, villous adenoma, mistake Structure tumor, liomyoma)；Urogenital tract, such as kidney (gland cancer, Wei Ermusishi tumour [nephroblastoma], lymthoma, white blood Disease), bladder and/or urethra (squamous cell carcinoma, transitional cell carcinoma, gland cancer), prostate (gland cancer, sarcoma), testis (spermatogonium Tumor, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell cancer, fibroma, adenofibroma, adenoma sample are swollen Tumor, lipoma)；Liver, for example, hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, adenoma, Hemangioma, endocrine tumor of pancreas (such as pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, islet-cell tumour and the high blood of pancreas Sugared element tumor)；Bone, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, You Wenshi Sarcoma, malignant lymphoma (reticulosarcoma), Huppert's disease, malignant giant cell tumor chordoma, osteochondroma (bone cartilage Epostoma), benign chondromas, chondrosarcoma, cartilage mucus fibroma, osteoidosteoma and giant-cell tumor；Nerveous system System, for example, central nervous system (CNS) anything superfluous or useless, primary CNS lymphoma, skull cancer (osteoma, hemangioma, granuloma, vitiligoidea, Scleromalacia), meninx (meningioma, meningosarcoma, gliomatosis), the cancer of the brain (astrocytoma, medulloblast Tumor, glioma, ependymoma, gonioma [pinealoma], glioblastoma multiforme, mesoglia Tumor, neurinoma, retinoblastoma, congenital tumor), intraspinal cord neurinomas, meningioma, glioma, meat Tumor)；Reproductive system, such as gynaecology, uterus (carcinoma of endometrium), cervix (cervical atypical hyperplasia before cervical carcinoma, tumour), ovum Nest (oophoroma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, non-categorical cancer], granulosa-thecoma, Sertoli-Leydig Cytoma, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, gland cancer, fibrosarcoma, melanin Tumor), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubal (carcinoma) He Yunv The associated other positions of sexual reproduction device；Placenta, penis, prostate, testis and other positions associated with male sex organ； Hematological system, such as (myelomatosis [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic are white for blood Blood disease, myeloproliferative disease, Huppert's disease, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma [malignant lymphoma]；Oral cavity, for example, lip, tongue, gum, mouth bottom, other portions, area of palate and oral area, the parotid gland and salivary gland its Other positions in its portion, area, tonsillotome, pars oralis pharyngis, pharynx nasalis, Pyriform sinus, hypopharynx and lip, oral cavity and pharynx；Skin, example Such as malignant mela noma, cutaneous melanoma, basal-cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplasia mole, rouge Fat tumor, hemangioma, histiocytoma and keloid；Adrenal gland: neuroblastoma；With other tissues, including connective tissue With soft tissue, retroperitoneal space and peritonaeum, eye, intraocular melanoma and adnexa, breast, head or/and neck, anal region, first shape Gland, parathyroid gland, adrenal gland and other endocrine glands and dependency structure, are exhaled at secondary and unspecified malignant lymph node anything superfluous or useless The secondary malignant neoplasm of the secondary malignant neoplasm and other positions of desorption system and digestive system.
More specifically, the example of cancer includes cancer selected from the following: lung cancer when using herein in conjunction with the present invention (NSCLC and SCLC), head or neck cancer, oophoroma, colon and rectum carcinoma, prostate cancer, anal region cancer, stomach cancer, mammary gland Cancer, kidney or carcinoma of ureter, clear-cell carcinoma, carcinoma of renal pelvis, central nervous system (CNS) anything superfluous or useless, primary CNS lymphoma, it is non-suddenly The combination of odd gold lymthoma and spinal column axis tumour or one or more aforementioned cancers.
In some embodiments, compound and composition disclosed herein can be used for treating cancer, including Si Picihei Plain tumor, neural surrounding wetting, lung maxicell neuroendocrine carcinoma, uterine cancer, juvenile breast cancer, nasopharyngeal carcinoma, adenoid cystic carcinoma, first Shape gland cephaloma, saliva cancer, congenital baby's fibrosarcoma, mesoblastic nephroma, cancer of the esophagus (squamous), the leaching of diffusivity large B cell Bar tumor, papillary thyroid carcinoma and mammary gland analog secrete cancer.
In some embodiments, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2, 2,2- tri- fluoro- 1,1- dimethyl ethyls) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) different evil of -3- Oxazolyl]-urea or its pharmaceutically acceptable salt pharmaceutical composition can with it is described below one or more other anti- Cancer agent is applied in combination.When using combination treatment, one or more other anticancer agents can be with the compound of the present invention sequence Or it is administered simultaneously.In some embodiments, before applying the compound of the present invention, other anticancer agent is applied to lactation Animal (such as people).In some embodiments, after applying the compound of the present invention, other anticancer agent is applied to lactation Animal.In some embodiments, other anticancer agent lactation is applied to while applying compound disclosed herein to move Object (such as people).
Some embodiments further relate to the pharmaceutical composition for the treatment abnormal cell growth in mammal (including people) Object, it includes a certain amount of N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl], [(2,2,2- tri- is fluoro- by 5- by-N'- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxies Base -4- quinazolyl) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its Pharmaceutically acceptable salt is (including the compound or its pharmaceutically hydrate of acceptable salt, solvate and more Crystal form object) pharmaceutical composition, be selected from anti-angiogenic agent and signal transduction in conjunction with one or more (preferably one to three kinds) and press down The anticancer agent of preparation, and pharmaceutically acceptable carrier, wherein activating agent and combination anticancer agent when taking as a whole Amount be that treatment is effective for treating the abnormal cell growth.
In some embodiments, the anticancer used in conjunction with compound disclosed herein and pharmaceutical composition as described herein Agent is anti-angiogenic agent (for example, the medicament for preventing tumor development new blood vessel).The example of anti-angiogenic agent includes for example VEGF inhibitor, VEGFR inhibitor, TIE-2 inhibitor, PDGFR inhibitor, angiogenin inhibitor, PKC beta inhibitor, COX-2 (cyclo-oxygenase II) inhibitor, integrin (α-v/ β -3), MMP-2 (matrix metalloproteinase 2) inhibitor and MMP-9 (matrix metalloproteinase 9) inhibitor.Preferred anti-angiogenic agent includes SutentBevacizumabAxitinib (AG13736), SU14813 (Pfizer) and AG13958 (Pfizer).
Other anti-angiogenic agent includes vatarani (CGP 79787), Sorafenib pegaptanib octasodiumVande ThaniPF-0337210(Pfizer)、SU 14843 (Pfizer), AZD 2171 (AstraZeneca), Lucentis (AE 941)、tetrathiomolybdataAMG 706(Amgen)、VEGF Trap(AVE 0005)、CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352) and CP-868,596 (Pfizer)。
Other anti-angiogenic agents include Enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), TeprenoneWith UCN 01 (Kyowa Hakko).
Can with N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, 1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxys - 4- quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its medicine The antiangiogenic agent that the pharmaceutical composition and pharmaceutical composition as described herein of the upper acceptable salt of object are used in combination Other examples include celecoxibParecoxibDeracoxib (SC 59046), Luo Mei Former times clothValdecoxibRofecoxibAilamodeIP 751 (Invedus), SC-58125 (Pharmacia) and 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl
Other anti-angiogenic agents include exisulind (exisulind)SalsalateDiflunisalBrufenKetoprofenNabumetonePiroxicamNaproxenDiclofenacIndomethacinSulindacMCN 2559EtodolacKetorolacWith olsapozine (oxaprozin)
Other anti-angiogenic agents include ABT 510 (Abbott), apratastat (TMI 005), 8955 (A Si of AZD Li Kang), incyclinideWith PCK 3145 (Procyon).
Other anti-angiogenic agents include A Qutingplitidepsin Cilengtide (EMD 121974), combretastatin A4 (CA4P), Suwei A amine (4HPR), Halofuginone(2ME2), PF-03446962 (Pfizer), Rui Masita (rebimastat) (BMS 275291), catumaxomabLenalidomideSqualamineThalidomide(NSC 631570)、(MEDI And zoledronic acid 522)
In some embodiments, anticancer agent is so-called signal transduction inhibitor (for example, inhibiting to adjust molecule domination carefully Intracellular growth, differentiation basic process and the mode for the survival being connected into the cell).Signal transduction inhibitor includes small molecule, antibody And antisense molecule.Signal transduction inhibitor includes such as kinase inhibitor (for example, tyrosine kinase inhibitor or serine/Soviet Union Histidine kinase inhibitor) and cell cycle inhibitor.More specifically, signal transduction inhibitor includes, such as ALK inhibitor, ROS1 inhibitor, TrkA inhibitor, TrkB inhibitor, TrkC inhibitor, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitor, MEK, c-Kit inhibitor, FLT-3 inhibitor, K-Ras inhibit Agent, PI3 kinase inhibitor, JAK inhibitor, STAT inhibitor, Raf kinase, Akt inhibitor, mTOR inhibitors, P70S6 kinase inhibitor, WNT approach restrainer and so-called more targeting kinase inhibitors.
Preferred signal transduction inhibitor includes GefitinibCetuximabAngstrom sieve replaces Buddhist nunTrastuzumabSutentImatinibWith PD325901 (Pfizer).
Its of the signal transduction inhibitor of compounds as disclosed herein and pharmaceutical composition described herein can be combined Its example includes BMS 214662 (Bristol-Myers Squibb), Luo Nafani (lonafarnib) Pelitrexol (AG 2037), matuzumab (EMD 7200), Buddhist nun's trastuzumab (TheraCIM h-), VictibixVande Thani: pazopanib (pazopanib) (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim) and(TP 38)。
Other examples of signal transduction inhibitor include PF-2341066 (Pfizer), PF-299804 (Pfizer), card how For Buddhist nun (CI 1033), handkerchief trastuzumabLapatinibpelitinib(EKB 569)、 MiltefosineBMS 599626(Bristol-Myers Squibb)、Lapuleucel-T(E75 cancer vaccine),(IDM 1), wood benefit replace Buddhist nun (TAK-165), CP- 724,714 (Pfizers), VictibixLapatinibPF-299804 (Pfizer), Pelitinib (EKB 569) and handkerchief trastuzumab
Other examples of signal transduction inhibitor include ARRY 142886 (Array Biopharm), everolimusZuo TamosiTamirosAP 23573 (ARIAD) and VX 680 (Vertex)。
In addition, other signals transduction inhibitor includes XL 647 (Exelixis), SorafenibLE- AON (Georgetown University) and GI-4000 (GlobeImmune).
Other signals transduction inhibitor includes ABT 751 (Abbott), alvocidib (Flavopiridol (flavopiridol))、BMS 387032(Bristol Myers)、EM 1421(Erimos)、indisulam(E 7070)、 seliciclib(CYC 200)、BIO 112(OneBio)、BMS 387032(Bristol-Myers Squibb)、PD 0332991 (Pfizer), AG 024322 (Pfizer), LOXO-101 (Loxo Oncology), gram azoles replace Buddhist nun (crizotinib) and Ceritinib (ceritinib).
In some embodiments, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2, 2,2- tri- fluoro- 1,1- dimethyl ethyls) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or comprising N- [3- [(6, 7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazole Base]-urea or its pharmaceutically the pharmaceutical composition of acceptable salt is used together with classical antitumor agent.Classical antitumor agent packet Include but be not limited to hormone regulator, such as hormone, antihormones, Androgen receptor agonists, androgen antagonist and anti-estrogen therapy Agent, histone deacetylase (HDAC) inhibitor, gene silencing agent or gene activator, ribalgilase, proteomics object Matter, topoisomerase I inhibitor, camptothecin derivative, Topoisomerase II inhibitors, alkylating agent, antimetabolite, poly- (ADP- Ribose) polymerase -1 (PARP-1) inhibitor, Antitubulin, antibiotic, the spindle poison of plant origin, platinum matches Position compound, gene therapeutic agents, antisense oligonucleotides, blood-vessels target agent (VTA) and statins.
For with N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1, 1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxys - 4- quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its medicine The pharmaceutical composition of the upper acceptable salt of object, it is optionally antitumor with the classics in the conjoint therapy of one or more other medicaments The example of agent includes, but are not limited to glucocorticoid, such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrogen Change cortisone and progestational hormone such as Medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), selective estrogen Receptor modulators (SERM；As tamoxifen, Raloxifene, lasofoxifene, A Fei former times fragrant (afimoxifene), A Zuopufen, Bazedoxifene, fispemifene, Ormeloxifene (ormeloxifene), Ao Pei meter Fen, tesmilifene, Toremifene, Qu Luo Take charge of adjustment (SERD under smooth (trilostane) and CHF 4227 (Cheisi), selective estrogen receptor；Such as fulvestrant), according to Xi Meitan (Aromasin), Anastrozole (Arimidex), atamestane (atamestane), Fadrozole (fadrozole), come Bent azoles (Femara)), gonadotropin-releasing hormone (GRH) (GnRH；Also commonly referred to as luteinising hormone-releasing hormo [LHRH]) excitement Agent such as Buserelin (Suprefact), Goserelin (Zoladex), Leuprorelin (Lupron) and Triptorelin (Trelstar), abarelix (Plenaxis), Bicalutamide (Casodex), cyproterone, Flutamide (Eulexin), first Progesterone, Nilutamide (Nilandron) and Osaterone (osaterone), dutasteride, epristeride (epristeride), Finasteride, sabal (Serenoa repens), PHL 00801, abarelix, Goserelin, Leuprorelin, Qu Purui Woods, Bicalutamide, tamoxifen, Exemestane, Anastrozole, Fadrozole, formestane, Letrozole and combinations thereof.
With N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- bis- of 2,2,2- tri- Methylethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxy-4 's-quinoline Oxazoline base) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its materia medica The other examples for the classical antitumor agent that the pharmaceutical composition of upper acceptable salt is used in combination include but is not limited to different hydroxyl oxime Sour (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, oxy acid methyl neopentyl butyrate and PXD-101；Ranpirnase (Onconase) (ranpirnase), PS-341 (MLN- 341), Velcade (bortezomib), 9-aminocamptothecin, Belotecan (belotecan), BN-80915 (Roche), camplotheca acuminata Alkali, Diflomotecan (diflomotecan), edotecarin, Exatecan (exatecan) (Daiichi), gefitinib (gimatecan), 10-hydroxycamptothecine, irinotecan hydrochloride (Camptosar), Lurtotecan (lurtotecan), Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecine, 10-hydroxycamptothecine, 9- amino camplotheca acuminata Alkali, Irinotecan, SN-38, edotecarin, topotecan, aclacinomycin, adriamycin, Amonafide (amonafide), Amrubicin, Anna mycin (annamycin), daunorubicin, adriamycin, Elsamitrucin, epirubicin, Etoposide, Yi Da Than star, galarubicin, hydroxycarbamide (hydroxycarbamide), Nemorubicin (nemorubicin), Novantrone (novantrone) (mitoxantrone (mitoxantrone)), pirarubicin, pixantrone (pixantrone), procarbazine (procarbazine), butterfly mycin, Sobuzoxane (sobuzoxane), tafluposide, valrubicin (valrubicin) S, Zinecard (dexrazoxane (dexrazoxane)), mustargen N- oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carbaxilquinone (carboquone), Ka Mosi Spit of fland, Chlorambucil, Dacarbazine, Estramustine, Fotemustine (fotemustine), glufosfamide (glufosfamide), Ifosfamide, KW-2170, lomustine, Mafosfamide (mafosfamide), mechlorethamine, melphalan, Mitobronitol, mitolactol (mitolactol), mitomycin C, mitoxantrone (mitoxatrone), Ni Mosi Spit of fland (nimustine), Ranimustine (ranimustine), Temozolomide (temozolomide), phosphinothioylidynetrisaziridine (thiotepa) and Platinum be coordinated alkylated compound such as cis-platinum, Paraplatin (carboplatin), eptalatin (eptaplatin), Lobaplatin (lobaplatin), how Up to platinum (nedaplatin), Eloxatin (oxaliplatin, Sino are luxuriant and rich with fragrance), streptozotocin, satrplatin and combinations thereof.
In some embodiments, N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2, 2,2- tri- fluoro- 1,1- dimethyl ethyls) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or comprising N- [3- [(6, 7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazole Base]-urea or its pharmaceutically acceptable salt pharmaceutical composition, be used together with following: dihydrofolate reductase inhibitor (such as methotrexate and NeuTrexin (glucuronic acid Trimetrexate)), purine antagonist (such as 6-MPR, mercapto Base purine, 6- thioguanine, Cladribine, clofarabine (Clolar), fludarabine, Buddhist nun draw shore and Raltitrexed), pyrimidine it is short of money Anti-agent (such as 5 FU 5 fluorouracil (5-FU), Alimta (pemetrexed disodium, LY231514, MTA), capecitabine Cytarabin,(gemcitabine, Eli Lilly), Tegafur (UFT Orzel or Uforal, including The TS-1 of Tegafur, gimestat and Otto department spy is combined), doxifluridine, Carmofur (carmofur), cytarabine (packet Include ocfosfate, phosphoric acid stearate, sustained release and liposomal form), enocitabine, 5-azacitidine (Vidaza), His shore of west and ethynylcytidine) and other antimetabolites such as Eflornithine, hydroxycarbamide, formyl tetrahydrofolic acid, Nola Qu Ke (Thymitaq), triapine, trimethoxy pterin (trimetrexate), N- (5- [N- (3,4- dihydro -2- methyl -4- oxo Quinazoline -6- ylmethyl)-N- methylamino] -2- Thenoyl)-Pidolidone, AG-014699 (Pfizer), ABT- 472(Abbott Laboratories)、INO-1001(Inotek Pharmaceuticals)、KU-0687(KuDOS ) and GPI 18180 (Guilford Pharm Inc) and combinations thereof Pharmaceuticals.
With N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- of 2,2,2- tri- Dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxy-4 's - Quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its drug The pharmaceutical composition of acceptable salt on, it is optionally anti-with classics used in the conjoint therapy of one or more other medicaments Cytotoxicity agent includes but is not limited to Abraxane (Abraxis BioScience Inc.), Ba Tabulin (Batabulin) (Amgen), EPO 906 (Novartis), Vinflunine (Bristol-Myers Squibb company), put Line rhzomorph D, bleomycin, mitomycin C, new nystatin (Zinostatin), vincaleukoblastinum, vincristine, eldisine, length Spring Rui Bin (Navelbine), Docetaxel (Taxotere), Ortataxel, taxol (including Taxoprexin and DHA/ Paclitaxel conjugate), cis-platinum, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), satraplatin, Camptosar, card training His shore (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, CanfosfamideDMXAA (Antisoma), ibandronic acid, L-ASP, Pegaspargase (pegaspargase)Efaproxiral(Radiotherapy), bexarotene (bexarotene)Tesmilifene (DPPE- enhances cytotoxic effect),(Biomira), TretinoinTirapazamineMotexafin gadolinium (motexafin gadolinium)(mAb) and NBI-3001 (Protox Therapeutics), polyglutamic acid-paclitaxelAnd combinations thereof.
With N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- of 2,2,2- tri- Dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxy-4 's - Quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its drug The pharmaceutical composition of acceptable salt on, it is optionally anti-with classics used in the conjoint therapy of one or more other medicaments The further example of tumour agent includes but is not limited to such as Advexin (ING201), TNFerade (GeneVec, response radiotherapy expression The compound of TNF α), RB94 (Baylor College Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer), general cut down him Spit of fland (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck company), Simvastatin (Zocor, Merck company), Fluvastatin (Lescol, Novartis), cerivastatin (cerivastatin) (Baycol, Bayer), Rosuvastatin (Rosuvastatin) (Crestor, AstraZeneca), Lovastatin (Lovastatin), niacin (Niacin) (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib and combinations thereof.
Some embodiments are related to the method that breast cancer is treated in the people for needing to treat in this way, including apply to the people A certain amount of N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (fluoro- 1,1- diformazan of 2,2,2- tri- Base ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxy-4 's-quinoline azoles Quinoline base) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically The pharmaceutical composition of acceptable salt, in conjunction with selected from following one or more (preferably one to three kind) anticancer agents: toltrazuril list Anti-, tamoxifen, Docetaxel, Paclitaxel, capecitabine, gemcitabine, vinorelbine, Exemestane, come it is bent Azoles and Anastrozole composition.
Some embodiments, which are provided, treats colorectal cancer in needing such mammal such as mankind treated Method is by combining one or more (preferably one to three kind) anticancer agents to apply a certain amount of N- [3- [(6,7- dimethoxies Base -4- quinazolyl) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its Pharmaceutically acceptable salt, or comprising N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2, The fluoro- 1,1- dimethyl ethyl of 2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt pharmaceutical composition.It is special The example for determining anticancer agent includes commonly used in those of adjuvant chemotherapy, such as FOLFOX, 5 FU 5 fluorouracil (5-FU) or card Train the combination of his shore (Xeloda), formyl tetrahydrofolic acid and oxaliplatin (Eloxatin).Other example packets of specific anticancer agent It includes commonly used in those of the chemotherapy of metastatic disease, such as FOLFOX or FOLFOX and bevacizumab (Avastin) group It closes；With the combination of FOLFIRI, 5-FU or capecitabine, formyl tetrahydrofolic acid and Irinotecan (Camptosar).Other examples Including 17-DMAG, ABX-EFR, AMG-706, AMT-2003, ANX-510 (CoFactor), aplidine (plitidepsin, Aplidin), Aroplatin, Axitinib (axitinib) (AG-13736), AZD-0530, AZD-2171, Bacillus Calmette-Guerin (BCG), Avastin (Avastin), BIO-117, BIO-145, BMS-184476, BMS- 275183, BMS-528664, bortezomib (Velcade), C-1311 (Symadex), not bank trastuzumab (Cantuzumab Mertansine), capecitabine (Xeloda), Cetuximab (Erbitux), clofarabine (Clofarex), CMD-193, Combretastatin (combretastatin), Cotara, CT-2106, CV-247, Decitabine (Dacogen), E-7070, E- 7820, edotecarin, EMD-273066, enzastaurin (LY-317615) epothilone B (EPO-906), Tarceva (Erlotinib), Flavopiridol (flavopyridol), GCAN-101, Gefitinib (Iressa), huA33, huC242-DM4, she Imatinib (Gleevec), indisulam, ING-1, Irinotecan (CPT-11, Camptosar) ISIS 2503, Ipsapirone, Lapatinib (Tykerb), Ma Pamu monoclonal antibody (Mapatumumab) (HGS-ETR1), MBT-0206, MEDI-522 (Abregrin), mitomycin, MK-0457 (VX-680), MLN-8054, NB-1011, NGR-TNF, NV-1020, oblimersen (Genasense, G3139), OncoVex, ONYX 015 (CI-1042), oxaliplatin (Eloxatin), Victibix (ABX- EGF, Vectibix), pelitinib (EKB-569), pemetrexed (Alimta), PD-325901, PF-0337210, PF- 2341066, RAD-001 (everolimus), RAV-12, resveratrol, Rexin-G, S-1 (TS-1), seliciclib, SN-38 Liposome, sodium gluconate (SSG), Sorafenib (Nexavar), SU-14813, Sutent (Sutent), tesirolimus (CCI 779), tetrathiomolybdate, husky sharp amine, TLK-286 (Telcyta), Hycamtin (Hycamtin), trabectedin (Yondelis), vatalanib (PTK-787), Vorinostat (SAHA, Zolinza), WX-UK1 and ZYC300, wherein activity The amount of agent effectively treats colorectal cancer together with the amount of combination anticancer agent.
Some embodiments provide the method that clear-cell carcinoma is treated in the mankind for needing such treatment, including to described [(2,2,2- tri- is fluoro- by 5- by-N'- by a certain amount of N- of human administration [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl] 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxies Base -4- quinazolyl) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its The pharmaceutically pharmaceutical composition of acceptable salt, in conjunction with one or more (preferably one to three kind) anticancer agents selected from the following: Capecitabine (Xeloda), interferon-' alpha ', interleukin 2, bevacizumab (Arastin), gemcitabine (Gemzar), sand Sharp degree amine, Cetuximab (Erbitux), vatarani (PTK-787), sotan (sutent), AG-13736, SU-11248, spy Luo Kai (Tarceva), Iressa (Iressa), Lapatinib (Lapatinib) and Gleevec (Gleevec), wherein activating agent Amount with combination anticancer agent amount together with effectively treat clear-cell carcinoma.
Some embodiments provide the method that melanoma is treated in the mankind for needing such treatment, including to described [(2,2,2- tri- is fluoro- by 5- by-N'- by a certain amount of N- of human administration [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl] 1,1- dimethyl ethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxies Base -4- quinazolyl) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its The pharmaceutically pharmaceutical composition of acceptable salt, in conjunction with one or more (preferably one to three kind) anticancer agents selected from the following: Interferon-' alpha ', interleukin 2, Temozolomide (Temodar), Docetaxel (Taxotere), Paclitaxel, Dacca Bar piperazine (DTIC), Carmustine (also referred to as BCNU), cis-platinum, vincaleukoblastinum, tamoxifen, PD-325,901, Axitinib, shellfish are cut down Monoclonal antibody (Arastin), Thalidomide, Sorafenib, vatarani (PTK-787), sotan, CpG-7909, AG-13736, easily Auspicious husky, Lapatinib and Gleevec, wherein the amount of activating agent effectively treats melanoma together with the amount of combination anticancer agent.
Some embodiments provide the methods that lung cancer is treated in the mankind for needing such treatment, including apply to the mankind With a certain amount of N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- bis- of 2,2,2- tri- Methylethyl) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt, or include N- [3- [(6,7- dimethoxy-4 's-quinoline Oxazoline base) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its materia medica The pharmaceutical composition of upper acceptable salt, in conjunction with one or more (preferably one to three kind) anticancer agents selected from the following: Ka Peita Shore (Xeloda), bevacizumab (Arastin), gemcitabine (Gemzar), Docetaxel (taxotere), Pacific yew Alcohol, preceding methotrexate (MTX) disodium (Alimta), Erlotinib, Iressa, vinorelbine, Irinotecan, Etoposide, vincaleukoblastinum and Paraplatin (carboplatin), wherein the amount of activating agent effectively treats lung cancer together with the amount of combination anticancer agent.
Some embodiments provide the method for treating the cancer including concrete type below: carcinoma, squamous cell Cancer, medullary system or lymphatic cells tumour, the tumour in mesenchyma source, tumour, melanoma, the essence of maincenter and peripheral neverous system Archaeocyte tumor, teratocarcinoma, osteosarcoma, angioderma pigmentosum, angiosarcoma, glioblastoma, cholangiocarcinoma, inflammatory flesh are fine Tie up blastoma, epithelioid hemangioendothelioma, astrocytoma, meningioma, angiosarcoma, epithelioid pericytoma (epitheloid hemangiothelioma), keratoacanthoma, thyroid follcular carcinoma, Kaposi's sarcoma and cancer of pancreas.
The method of cancer of the following embodiments offer for treating concrete type such as, but not limited to, below: breast cancer, Lung cancer, colorectal cancer, prostate cancer, oophoroma, carcinoma of endometrium, gastric cancer, clear cell renal cell carcinoma, invasive ductal carcinoma (breast), uveal, Huppert's disease, rhabdomyosarcoma, ewing's sarcoma, Kaposi's sarcoma, cancer of pancreas And medulloblastoma.
Molecule screening
Transcribing accumulating level, genomic locus screening technique and the protein kinase activity measurement for RET can be used Method known to those skilled in the art carries out.It can be swashed by providing substrate to the protein extract comprising RET Enzymatic determination.The sequencing of RET locus can be used such as sequencing of full-length genome air gun or the targeting of RET locus and be sequenced to carry out, Such as what is generated by using round pcr well known by persons skilled in the art and by methods known to those skilled in the art draws Object carries out all or part of targeting amplification to locus or across the region of locus, then to the amplicon of any generation It is sequenced.(NGS), quantitative reverse transcription polymerase chain reaction dna amplified reaction (qPCR), fluorescence original can be sequenced by the next generation Position hybridization (FISH) and/or immunohistochemistry (IHC) detection molecules change, and polymorphic including gene rearrangement, single nucleotide acid Property (SNP), insertion, missing, splice variant, gene magnification and aberrant RNAs/protein expression.
Copy number variation (CNV), point mutation (SNP/SNV), insertion, missing, gene rearrangement, RNA/ protein overexpression and Composing type phosphorylation is measurable variation, can lead to carcinogenic disturbance RET, for example, mistake is adjusted, up-regulation or lower until and Activity is completely lost including being adjusted downward to.Test based on DNA can detecte CNV, SNP, insertion, missing and gene rearrangement.It is based on The test of RNA can detecte overexpression, expression is insufficient (until and including completely losing expression) or the false demonstration of RET mRNA And many changes detected in the test based on DNA.Test based on protein, which allows to measure, to be overexpressed, expresses deficiency The expression mistake of (until and including completely losing expression) or RET albumen；Composing type phosphorylation, composing type dephosphorylation or RET The wrong phosphorylation of albumen；And increase, reduction (until and including completely losing) or the active patterns of RET kinase activity change Become.
Embodiment 1: application N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea to implantation have various RET Gene Fusions cell mammal.
To have (a) NCOA4-RET (colorectal cancer specimens) Gene Fusion, (b) CCDC6-RET Gene Fusion (colon Carcinoma of the rectum sample), or (c) the swelling from subject of one of KIF5B-RET Gene Fusion (non-small cell lung cancer sample) In the cell implantation Mice Body of tumor sample.Then excipient is applied to mouse or contain 30mg/kg N- [3- [(6,7- dimethoxy Base -4- quinazolyl) oxygroup] phenyl] and-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea system Agent, twice daily.The gross tumor volume of periodic measurement mouse.
Fig. 1 shows result of study, wherein mean tumour volume (the mm of mouse3) draw on the y axis, treatment number of days is drawn In x-axis.Apply N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (fluoro- 1,1- of 2,2,2- tri- Dimethyl ethyl) -3- isoxazolyl]-urea mouse in tumour than apply carrier mouse in tumour growth it is slower.
Embodiment 2: hydrochloric acid N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea preparation.
N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- is added into reactor Three fluoro- 1,1- dimethyl ethyls) -3- isoxazolyl]-urea free alkali and anhydrous tetrahydro furan (THF).It is stirred to react mixture simultaneously It is heated to about 45 DEG C and is maintained at the temperature until obtaining solution.After carrying out polishing filtering to solution, add at about 45 DEG C 2- propyl alcohol (IPA) solution for entering preformed pre-filtered hydrogen chloride, causes solid to precipitate.Mixture is stirred at such a temperature It mixes at least 1 hour.Mixture is cooled to about 0 DEG C and is filtered.The THF that filter cake precools is washed, is dried under vacuum simultaneously Deblocking, obtains hydrochloric acid N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1,1- Dimethyl ethyl) -3- isoxazolyl]-urea.
Embodiment 3: comprising hydrochloric acid N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2, The fluoro- 1,1- dimethyl ethyl of 2- tri-) -3- isoxazolyl]-urea capsule.
Prepare capsule comprising 25 milligrams or 75 milligrams hydrochloric acid N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygen Base] phenyl] figuration in-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea and the following table 1 and 2 Agent.
Table 1.
(N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- of * 26.75mg Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea hydrochloride is equivalent to N- [3- [(the 6,7- diformazan of each capsule 25.00mg Oxygroup -4- quinazolyl) oxygroup] phenyl] trip of-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea From alkali)
Table 2.
(N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- of * 80.25mg Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea hydrochloride is equivalent to N- [3- [(the 6,7- diformazan of each capsule 75.00mg Oxygroup -4- quinazolyl) oxygroup] phenyl] trip of-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea From alkali)
By hydrochloric acid N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- of sieving Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea and a part of magnesium stearate mix.By hydroxy propyl-Beta cyclodextrin With Explotab (SSG) and the hydrochloric acid N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea/magnesium stearate pre-composition is mixed into suitable mixer And it mixes.It is then that mixture sieving, mixing and re-sieving is primary.The magnesium stearate of remainder is added in mixture, and Gained mixture is mixed.Final mixture is sampled to determine that mixing uniformity is filled suitably using capsule filling machine Capsule, then dedusting, and capsules weight is checked using suitable weight check device.Then gained capsule is packaged into suitable appearance In device.
Embodiment 4: application N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea is in RET to there is the subject of genetic change.
The clinical research of I phase and Ib phase are carried out, wherein registration has 92 subjects altogether, wherein 91 are treated, and Wherein be confirmed as at 35 of the phase part Ib can molecular evaluation and treated.Table 3 provides the participation I phase and the Ib phase grinds Those of study carefully the Subject characteristics of subject and the summary of disposition.Subject is oral to give capsule, and capsule includes 25mg or 75mg Hydrochloric acid N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (fluoro- 1,1- dimethyl of 2,2,2- tri- Ethyl) -3- isoxazolyl]-urea, similar to those of described in embodiment 3.The initial dose that subject receives is equivalent to N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] benzene of 275mg or 350mg dosage (being calculated with the amount of free alkali) Base]-N'- [5- (2,2,2- tri- fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea, (QD), and subject once a day In the eating state lower administration.
Table 3.
The most common treatment-related adverse events (AE) is total in all patients (n=91) that the offer of table 4 is treated It ties (percentage for being expressed as 91 patients).
Table 4.
Grade≤2 Grade >=3 Any grade
Fash * 20(22) 8(9) 28(31)
Fatigue 16(18) 4(4) 20(22)
Diarrhea 14(15) 4(4) 18(20)
Nausea 16(18) 0 16(18)
Hypophosphatemia 7(8) 6(7) 13(14)
Vomiting 13(14) 0 13(14)
Muscle cramp 12(13) 0 12(13)
Loss of appetite 9(10) 0 9(10)
Erythema 7(8) 0 7(8)
ALT increases 1(1) 5(6) 6(7)
Anaemia 5(6) 1(1) 6(7)
AST increases 3(3) 3(3) 6(7)
Hypopotassaemia 6(7) 0 6(7)
Dysgeusia 5(6) 0 5(6)
* include 13 grades of fash, be diagnosed as the drug response of eosinophilia and constitutional symptom, suffer from wherein being discontinued Person restores and 13 grades of fash merges lethal alveolar bleeding
Table 5 provides the summary for participating in 12 subjects for being confirmed as having RET to merge that the Ib phase is studied.Determine 8 by Examination person is RET inhibitor initial treatment, and 4 subjects are determined not to be RET inhibitor initial treatment
Table 5.
Fig. 2 is in the RET fusion positive subjects for the RET- inhibitor initial treatment for showing that participation I phase and Ib phase are studied The Waterfall plot of best tumor response.Note that Fig. 2 include 8 subjects studied from the Ib phase and study from the I phase 1 by Examination person, the subject are determined to have NCOA4-RET Gene Fusion and with metastatic colorectal cancers.What subject received Initial dose is equivalent to N- [3- [(the 6,7- dimethoxy-4 '-quinoline azoles of 275mg or 350mg dosage (calculating with the amount of free alkali) Quinoline base) oxygroup] phenyl]-N'- [5- (2,2,2- tri- fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea, once a day (QD), and subject is in the eating state administered down.In Fig. 2, y-axis indicate in each subject target lesion (tumour) size with The percentage of baseline changes.The details about each subject is drawn along x-axis, determines the specific heredity having including subject Change (" RET fusion "), duration for the treatment of (" DOT ") and duration of response (" DOR ").Labeled as the void of " PR " and " CR " Line indicates composition part reaction (" PR ") or tumor size completely in subject necessary to reaction (" CR ") under RECIST standard Reduction.With being labeled as 20,0.3, (- 10), (- 32), (- 52), the subject of the reaction of (- 60) and (- 77) is with non-small Cell lung cancer (NSCLC).Metastatic colorectal cancer is suffered from the subject labeled as 20 and the reaction of (- 100).It grinds at this In studying carefully, the general reaction rate for being determined as the subject of the positive RET inhibitor initial treatment of RET fusion be determined as 56% (9 by 5 in examination person).
Embodiment 5: application N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2,2,2- tri- Fluoro- 1,1- dimethyl ethyl) -3- isoxazolyl]-urea is in RET to there is the subject of genetic change.
I phase and Ib phase clinical research are carried out, wherein 152 subjects are given the N- [3- of more than one dosage altogether [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) different evil of -3- Oxazolyl]-urea.Table 6, which is provided, those of studies the subject of subject by the participation I phase of the data on the 1st of August in 2017 and Ib phase The summary of feature and disposition.In 152 patients, the oral N- for giving the 275mg in pharmaceutical preparation of 74 patients's (49%) [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- Isoxazolyl]-carbamide compound, in the eating state under once a day.
Table 6.
Most of treatment-related adverse events (AE) are respectively≤2 grades and are reversible under dosage modification.13 trouble Person's (9%) experienced 19 times and treatment-related serious adverse events (SAE), all adjusts or stops by dosage in addition to 1 patient It is solved after medicine.Toxicity usually relevant to VEGFR inhibition, such as hypertension, hypothyroidism, albuminuria and neurotoxicity Seldom it is observed.It is unrelated with QT/QTc extension that compound is given under these conditions.By the data cut-off on the 1st of August in 2017 Most common (> 10%) treatment correlation AE be shown in Table 7.
Table 7.
* fash, fash erythema, fash whole body, fash macula lutea, Rash maculo-papular, papular papule, Rash The drug rash of pruritic, nettle rash, eosinophil and constitutional symptom, drug allergy, adverse drug reaction.
The RET- fusion that Fig. 3 is shown in the RET- inhibitor initial treatment with non-small cell lung cancer (NSCLC) is positive N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygen] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl second of 2,2,2- tri- in patient Base) -3- isoxazolyl]-urea anti-tumor activity Waterfall plot.Each bar shaped represents single patient (22 patients in total).Generation There are table the bar-shaped marks of the patient of CCDC6-RET fusion, PARD3-RET fusion or EML4-RET fusion to have specific fusion.It is surplus Remaining unmarked bar shaped represents the patient with KIF5B-RET fusion.Y-axis indicates largest percentage of the target lesion summation from baseline Variation.In the patient with non-KIF5B-RET fusion (n=8), 75% there is part to react.Melt with KIF5-B-RET In the patient for closing (n=14), 3 have and continue 6 months or the stable disease of longer time.In addition, suffering from metastatic Colon and rectum Controlling patient at the beginning of cancer and the RET- inhibitor merged with CCDC6-RET realizes complete response and by August 1st, 2017 Data Expiration continues to study.
Conclusion in research is as follows.N- [3- [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (2, The fluoro- 1,1- dimethyl ethyl of 2,2- tri-) -3- isoxazolyl]-urea late or in metastatic solid tumors patient show it is controllable Safety.It is initial with 22 (22) name RET fusion positive of 275mg or 350mg dosage treatment once a day, RET inhibitor Effect can be evaluated in the NSCLC patient for the treatment of.Wherein, RET fusion partner of 8 patients' carryings in addition to KIF5B, including CCDC6, EML4 and PARD3.The overall reaction rate (ORR) of non-KIF5B-RET fusion patient is 75% (95%CI:34.9%-96.8%).Separately Outside, 1 patient has stable disease in about 6 treatment cycles.The middle position duration of the reaction of these patients has not yet been reached (DOR), longest DOR is 10.2 months.In the patient that other 14 carry KIF5B-RET fusion, no an example patient has RECIST reaction, although the stable disease of 3 patients continues 6 months or the longer time.Match with KIF5B and non-KIF5B fusion This response difference between the tumour of even body with previously with other RET activating agents to collect effect evidence consistent, show KIF5B-RET fusion may be less susceptible to by targeted inhibition.
Term " includes " as used herein and "comprising", " containing " or " being characterized in that " it is synonymous, and be inclusive Or it is open and be not excluded for other unlisted element or method and step.
All numbers of the amount used in the description such as expression composition, reaction condition should be correspondingly interpreted as in institute It is modified under there is something special by term " about ", unless stated otherwise, numerical parameter as described herein is approximation, can be according to attempting Obtain required property and change.At least and not attempt for the application of doctrine of equivalents to be limited in the priority for requiring the application Any application in any the scope of the claims, each numerical parameter should be according to number of significant figures and common rounding-off Method is explained.
Above description discloses several method and material of the invention.The present invention be easy to modify to method and material with And manufacturing method and equipment are changed.By considering the practice of the disclosure or present invention disclosed herein, these modifications pair It will become obvious for those skilled in the art.Therefore, the present invention is not limited to specific embodiment party disclosed herein Case, but cover all modifications fallen within the true scope and spirit of the present invention and alternative solution.
All references cited herein, including but not limited to announcement and non-published application, patent and bibliography, all It is incorporated herein by reference in their entirety, and in this as a part of this specification.If the publication being incorporated by reference into and specially Benefit or patent application and specification in include disclosure contradict, then specification be intended to substitution and/or prior to it is any this The contradiction material of sample.

Claims (17)

1. a kind of method of subject of the treatment with cancer, the N- [3- including applying therapeutically effective amount to the subject [(6,7- dimethoxy-4 '-quinazolyl) oxygroup] phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) different evil of -3- Oxazolyl]-urea or its pharmaceutically acceptable salt, wherein before the application of the compound, it is known that subject's tool Have at least one of RET genetic change, and wherein at least one of RET genetic change be selected from NCOA4-RET fusion, The gene of KIF5B-RET fusion, CCDC6-RET fusion, EML4-RET fusion, PARD3-RET fusion and CLIP1-RET fusion melts It closes.
2. according to the method described in claim 1, wherein the Gene Fusion is CCDC6-RET fusion.
3. according to the method described in claim 1, wherein the Gene Fusion is EML4-RET fusion.
4. according to the method described in claim 1, wherein the Gene Fusion is PARD3-RET fusion.
5. according to the method described in claim 1, wherein described N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] benzene Base]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt be with every The amount of its about 100mg to about 1000mg are applied to the subject.
6. according to the method described in claim 1, wherein in application N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] Phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt are extremely Subject's foregoing description subject is that RET inhibitor was not treated.
7. according to the method described in claim 1, wherein in application N- [3- [(6,7- dimethoxy-4 's-quinazolyl) oxygroup] Phenyl]-N'- [5- (the fluoro- 1,1- dimethyl ethyl of 2,2,2- tri-) -3- isoxazolyl]-urea or its pharmaceutically acceptable salt are extremely Subject's foregoing description subject is not that RET inhibitor was not treated.
8. according to the method described in claim 1, wherein the cancer in the subject be selected from colorectal cancer, lung cancer, Non-small cell lung cancer, thyroid cancer and medullary carcinoma of thyroid gland.
9. according to the method described in claim 8, wherein the cancer in the subject is colorectal cancer.
10. according to the method described in claim 9, wherein the colorectal cancer in the subject is metastatic colon The carcinoma of the rectum.
11. according to the method described in claim 8, wherein the cancer in the subject is lung cancer.
12. according to the method described in claim 8, wherein the cancer in the subject is non-small cell lung cancer.
13. according to the method described in claim 8, wherein the cancer in the subject is thyroid cancer.
14. according to the method described in claim 8, wherein the cancer in the subject is medullary carcinoma of thyroid gland.
15. according to the method described in claim 1, wherein the cancer in the subject is solid tumor or liquid tumors.
16. according to the method for claim 15, wherein the cancer in the subject is solid tumor.
17. according to the method for claim 15, wherein the cancer in the subject is liquid tumors.
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